Thieno-pyridine derivatives as mek inhibitors

ABSTRACT

A series of thieno[2,3-b]pyridine derivatives which are substituted in the 2-position by a substituted anilino moiety, being selective inhibitors of human MEK (MAPKK) enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, proliferative (including oncological) and nociceptive conditions.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a continuation of International ApplicationNo.: PCT/GB2007/000310, filed Jan. 30, 2007, which claims priority under119(a-d) to Great Britain Application No. GB 0601962.4, filed 31, Jan.2006. Each of these applications is hereby incorporated herein byreference in their entireties.

The present invention relates to a class of thieno-pyridine derivativesand to their use in therapy. More particularly, the invention isconcerned with thieno[2,3-b]pyridine derivatives which are substitutedin the 2-position by a substituted anilino moiety. These compounds areselective inhibitors of MEK (MAPKK) enzymes, and are accordingly ofbenefit as pharmaceutical agents, especially in the treatment of adverseinflammatory, autoimmune, cardiovascular, proliferative (includingoncological) and nociceptive conditions.

MEK enzymes are implicated in a variety of physiological andpathological functions that are believed to be operative in a range ofhuman diseases. These functions are summarised in paragraphs [0004] and[0005] of US 2005/0049276 A1.

The compounds of use in the present invention, being potent andselective MEK inhibitors, are therefore beneficial in the treatmentand/or prevention of various human ailments. These include autoimmuneand inflammatory disorders such as rheumatoid arthritis, osteoarthritis,multiple sclerosis, asthma, inflammatory bowel disease, psoriasis andtransplant rejection; cardiovascular disorders including thrombosis,cardiac hypertrophy, hypertension, and irregular contractility of theheart (e.g. during heart failure); proliferative disorders such asrestenosis, and oncological conditions including leukaemia,glioblastoma, lymphoma, melanoma, and human cancers of the liver, bone,skin, brain, pancreas, lung, breast, stomach, colon, rectum, prostate,ovary and cervix; and pain and nociceptive disorders, including chronicpain and neuropathic pain.

In addition, the compounds of use in the present invention may bebeneficial as pharmacological standards for use in the development ofnew biological tests and in the search for new pharmacological agents.Thus, the compounds of use in this invention may be useful asradioligands in assays for detecting compounds capable of binding tohuman MEK enzymes.

MEK inhibitors based on a fused bicyclic aromatic ring system attachedto a substituted anilino moiety are known from the art. Examples ofrelevant publications include WO 2005/051906, WO 2005/023251,US-A-2005/0049276, WO 2005/009975, WO 03/077914 and WO 03/077855.

WO 2005/023818 describes a broad-ranging class of compounds based on afused bicyclic aromatic ring system, which generically encompassesthieno-pyridine derivatives attached to a substituted anilino moiety butnowhere specifically discloses any precise compound of this type. Nodiscrete pharmacological activity, in terms of an identifiablepharmacological mechanism, is ascribed to the compounds describedtherein, but they are nevertheless stated to be useful inter alia in thetreatment of cell proliferative diseases such as cancer.US-A-2003/0220365 is also of relevance in a related context.

Nowhere in the prior art, however, is there the precise disclosure of aclass of thieno[2,3-b]pyridine derivatives attached at the 2-position toa substituted anilino moiety. It has now been found that such compoundsare particularly valuable as selective inhibitors of MEK enzymes.

The compounds of the present invention are potent and selective MEKinhibitors having a binding affinity (IC₅₀) for the human MEK1 and/orMEK2 enzyme of 50 μM or less, generally of 20 μM or less, usually of 5μM or less, typically of 1 μM or less, suitably of 500 nM or less,ideally of 100 nM or less, and preferably of 20 nM or less (the skilledperson will appreciate that a lower IC₅₀ figure denotes a more activecompound). The compounds of the invention may possess at least a 10-foldselective affinity, typically at least a 20-fold selective affinity,suitably at least a 50-fold selective affinity, and ideally at least a100-fold selective affinity, for the human MEK1 and/or MEK2 enzymerelative to other human kinases.

The present invention provides a compound of formula (I), or apharmaceutically acceptable salt, solvate or N-oxide thereof:

wherein

R¹ represents hydrogen, halogen or C₁₋₆ alkyl;

R² represents halogen or C₁₋₆ alkyl;

R³ represents hydrogen, cyano, —CO₂R^(a), —CONR^(b)R^(c) or—CON(OR^(b))R^(c);

R^(a) represents C₁₋₆ alkyl;

R^(b) represents hydrogen; or C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl(C₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl,C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl,any of which groups may be optionally substituted by one or moresubstituents; and

R^(c) represents hydrogen or C₁₋₆ alkyl (optionally substituted byhydroxy); or

R^(b) and R^(c), when taken together with the nitrogen atom to whichthey are both attached, represent azetidinyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl,homomorpholinyl or homopiperazinyl, any of which groups may beoptionally substituted by one or more substituents.

The present invention also provides a compound of formula (I) asdepicted above, or a pharmaceutically acceptable salt, solvate orN-oxide thereof, wherein

R¹ and R² are as defined above;

R³ represents cyano, —CO₂R^(a), —CONR^(b)R^(c) or —CON(OR^(b))R^(c);

R^(a) represents C₁₋₆ alkyl;

R^(b) represents hydrogen; or C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyl(C₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl,C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl,any of which groups may be optionally substituted by one or moresubstituents; and

R^(c) represents hydrogen or C₁₋₆ alkyl; or

R^(b) and R^(c), when taken together with the nitrogen atom to whichthey are both attached, represent azetidinyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, homopiperidinyl orhomomorpholinyl, any of which groups may be optionally substituted byone or more substituents.

For use in medicine, the salts of the compounds of formula (I) will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds of the invention or of theirpharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compounds of this invention include acid addition saltswhich may, for example, be formed by mixing a solution of the compoundof the invention with a solution of a pharmaceutically acceptable acidsuch as hydrochloric acid, sulphuric acid, methanesulphonic acid,fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid,citric acid, tartaric acid or phosphoric acid. Furthermore, where thecompounds of the invention carry an acidic moiety, e.g. carboxy,suitable pharmaceutically acceptable salts thereof may include alkalimetal salts, e.g. sodium or potassium salts; alkaline earth metal salts,e.g. calcium or magnesium salts; and salts formed with suitable organicligands, e.g. quaternary ammonium salts.

The present invention includes within its scope solvates of thecompounds of formula (I) above. Such solvates may be formed with commonorganic solvents, e.g. hydrocarbon solvents such as benzene or toluene;chlorinated solvents such as chloroform or dichloromethane; alcoholicsolvents such as methanol, ethanol or isopropanol; ethereal solventssuch as diethyl ether or tetrahydrofuran; or ester solvents such asethyl acetate. Alternatively, the solvates of the compounds of formula(I) may be formed with water, in which case they will be hydrates.

Suitable alkyl groups which may be present on the compounds of theinvention include straight-chained and branched C₁₋₆ alkyl groups, forexample C₁₋₄ alkyl groups. Typical examples include methyl and ethylgroups, and straight-chained or branched propyl, butyl and pentylgroups. Particular alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and2,2-dimethylpropyl. Derived expressions such as “C₁₋₆ alkoxy”, “C₁₋₆alkylthio”, “C₁₋₆ alkylsulphonyl” and “C₁₋₆ alkylamino” are to beconstrued accordingly.

Specific C₃₋₇ cycloalkyl groups are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

Suitable aryl groups include phenyl and naphthyl, preferably phenyl.

Suitable aryl(C₁₋₆)alkyl groups include benzyl, phenylethyl,phenylpropyl and naphthylmethyl.

Suitable heterocycloalkyl groups, which may comprise benzo-fusedanalogues thereof, include azetidinyl, tetrahydrofuranyl, dioxolanyl,pyrrolidinyl, indolinyl, imidazolidinyl, tetrahydropyranyl, piperidinyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,piperazinyl, morpholinyl and thiomorpholinyl.

Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl,thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl,pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl andpyrazinyl groups.

The term “halogen” as used herein is intended to include fluorine,chlorine, bromine and iodine atoms.

Where the compounds of formula (I) have one or more asymmetric centres,they may accordingly exist as enantiomers. Where the compounds of theinvention possess two or more asymmetric centres, they may additionallyexist as diastereomers. The invention is to be understood to extend toall such enantiomers and diastereomers, and to mixtures thereof in anyproportion, including racemates. Formula (I) and the formulae depictedhereinafter are intended to represent all individual stereoisomers andall possible mixtures thereof, unless stated or shown otherwise. Inaddition, compounds of formula (I) may exist as tautomers, for exampleketo (CH₂C═O)-enol (CH═CHOH) tautomers. Formula (I) and the formulaedepicted hereinafter are intended to represent all individual tautomersand all possible mixtures thereof, unless stated or shown otherwise.

In one embodiment, R¹ represents hydrogen. In another embodiment, R¹represents halogen, particularly fluoro or chloro, especially fluoro. Ina further embodiment, R¹ represents C₁₋₆ alkyl, especially methyl.

Typically, R¹ is fluoro.

In one embodiment, R² represents halogen, especially bromo or iodo. Inanother embodiment, R² represents C₁₋₆ alkyl, especially methyl.

In one specific embodiment, R² is bromo. In another specific embodiment,R² is iodo.

Suitably, R^(a) represents methyl or ethyl, especially ethyl.

Favourably, R^(b) represents hydrogen; or C₁₋₆ alkyl, C₃₋₇cycloalkyl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl or C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, any of which groups may be optionallysubstituted by one or more substituents.

Suitably, R^(b) represents hydrogen; or C₁₋₆ alkyl, aryl,aryl(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any ofwhich groups may be optionally substituted by one or more substituents.

Suitably, the group R^(b), or the cyclic moiety —NR^(b)R^(c), may beunsubstituted, or substituted by one or more substituents, typically byone or two substituents. In one embodiment, the group R^(b), or thecyclic moiety —NR^(b)R^(c), is unsubstituted. In another embodiment, thegroup R^(b), or the cyclic moiety —NR^(b)R^(c), is monosubstituted. In afurther embodiment, the group R^(b), or the cyclic moiety —NR^(b)R^(c),is disubstituted.

Examples of typical substituents on R^(b), or on the cyclic moiety—NR^(b)R^(c), include C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy,hydroxy(C₁₋₆)alkyl, amino(C₁₋₆)alkyl, (amino)(hydroxy)-(C₁₋₆)alkyl,halogen, oxo, C₂₋₆ alkylcarbonyl, carboxy, C₂₋₆ alkoxycarbonyl,di(C₁₋₆)alkylhydrazinylcarbonyl, amino, C₁₋₆ alkylamino,di(C₁₋₆)alkylamino, C₂₋₆ alkylcarbonylamino, aminocarbonylamino,aminocarbonyl, C₁₋₆ alkylaminocarbonyl, di(C₁₋₆)alkylaminocarbonyl,aminosulfonyl, C₁₋₆ alkylsulfonyl and C₁₋₆alkylaminocarbonyl(C₁₋₆)alkyl. Further examples include C₁₋₆alkoxy(C₁₋₆)alkyl, carboxy(C₁₋₆)alkyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl,C₂₋₆ alkoxycarbonylamino and C₂₋₆ alkoxycarbonylamino(C₁₋₆)alkyl.

Examples of particular substituents on R^(b), or on the cyclic moiety—NR^(b)R^(c), include methyl, methoxy, hydroxy, hydroxymethyl,2-hydroxyethyl, aminomethyl, 2-amino-3-hydroxypropyl, fluoro, oxo,acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,dimethylhydrazinylcarbonyl, amino, methylamino, 1,3-dimethyl-butylamino,dimethylamino, acetylamino, aminocarbonylamino, aminocarbonyl,ethylaminocarbonyl, diethylaminocarbonyl, aminosulfonyl, methylsulfonyland methylaminocarbonylmethyl. Further examples include methoxymethyl,carboxymethyl, ethoxycarbonylmethyl, tert-butoxycarbonylamino andtert-butoxycarbonylaminomethyl.

Examples of favoured substituents on R^(b), or on the cyclic moiety—NR^(b)R^(c), include C₁₋₆ alkyl, C₁₋₆ alkoxy(C₁₋₆)alkyl, hydroxy,hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl, carboxymethyl, C₂₋₆alkoxycarbonyl, C₂₋₆ alkoxycarbonyl(C₁₋₆)alkyl, di(C₁₋₆)alkylamino, C₂₋₆alkoxycarbonylamino and C₂₋₆ alkoxycarbonylamino(C₁₋₆)alkyl. [00011]Examples of specific substituents on R^(b), or on the cyclic moiety—NR^(b)R^(c), include methyl, methoxymethyl, hydroxy, hydroxymethyl,2-hydroxyethyl, amino, aminomethyl, carboxymethyl, tert-butoxycarbonyl,ethoxycarbonylmethyl, dimethylamino, tert-butoxycarbonylamino andtert-butoxycarbonylaminomethyl.

Favoured values of R^(b) include hydrogen, methyl, ethyl, propyl,cyclopropylmethyl, azetidinyl, pyrrolidinyl, piperidinyl,azetidinylmethyl, dioxolanylmethyl, pyrrolidinylmethyl, morpholinylethyland morpholinylpropyl, any of which groups may be optionally substitutedby one or more substituents. Favoured substituents in this contextinclude C₁₋₆ alkyl (especially methyl), hydroxy, amino, C₂₋₆alkoxycarbonyl (especially tert-butoxycarbonyl) and di(C₁₋₆)alkylamino(especially dimethylamino).

Specific values of R^(b) include hydrogen, methyl, 2-hydroxyethyl,3-hydroxypropyl, 1-hydroxyprop-2-yl, 2,3-dihydroxypropyl,2-amino-2-methylpropyl, 2,2-dimethyl-3-(dimethylamino)propyl,cyclopropylmethyl, 1-tert-butoxycarbonylazetidin-3-yl, pyrrolidin-3-yl,1-tert-butoxycarbonylpyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl,1-methylpiperidin-4-yl, 1-tert-butoxycarbonylpiperidin-3-yl,1-tert-butoxycarbonylpiperidin-4-yl,1-tert-butoxycarbonylazetidin-3-ylmethyl,2,2-dimethyl-[1,3]dioxolan-4-ylmethyl, pyrrolidin-2-ylmethyl,2-(morpholin-4-yl)ethyl and 3-(morpholin-4-yl)propyl.

Typically, R^(b) represents hydrogen; or C₁₋₆ alkyl, optionallysubstituted by one or more, preferably one or two, hydroxy groups.

Typical values of R^(b) include hydrogen, methyl, hydroxypropyl anddihydroxypropyl. In one embodiment, R^(b) represents hydrogen. Inanother embodiment, R^(b) represents methyl. In a further embodiment,R^(b) represents hydroxypropyl, especially 3-hydroxypropyl. In anadditional embodiment, R^(b) represents dihydroxypropyl, especially2,3-dihydroxypropyl.

In one embodiment, R^(c) is hydrogen. In another embodiment, R^(c)represents C₁₋₆ alkyl, especially methyl. In a further embodiment, R^(c)represents hydroxy(C₁₋₆)alkyl, e.g. hydroxyethyl (especially2-hydroxyethyl).

Alternatively, the moiety —NR^(b)R^(c) may suitably representazetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl orhomomorpholin-4-yl, any of which groups may be optionally substituted byone or more substituents. The moiety —NR^(b)R^(c) may also representoptionally substituted homopiperazin-1-yl.

Particular values for the cyclic moiety —NR^(b)R^(c) includeazetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,piperazin-1-yl and homopiperazin-1-yl, any of which groups may beoptionally substituted by one or more substituents.

Specific values of the cyclic moiety —NR^(b)R^(c) include3-hydroxyazetidin-1-yl, 3-aminoazetidin-1-yl,3-(aminomethyl)azetidin-1-yl,3-(tert-butoxycarbonylamino)-azetidin-1-yl,3-(tert-butoxycarbonylaminomethyl)azetidin-1-yl, pyrrolidin-1-yl,2-(methoxymethyl)pyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl,3-amino-pyrrolidin-1-yl, 3-(tert-butoxycarbonylamino)pyrrolidin-1-yl,2-(hydroxymethyl)-piperidin-1-yl, 4-aminopiperidin-1-yl,4-(tert-butoxycarbonylamino)piperidin-1-yl, morpholin-4-yl,2-(hydroxymethyl)morpholin-4-yl, piperazin-1-yl, 4-methylpiperazin-1-yl,2-(hydroxymethyl)-piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl,4-(carboxy-methyl)piperazin-1-yl,4-(tert-butoxycarbonyl)-2-(hydroxymethyl)piperazin-1-yl,4-(ethoxycarbonylmethyl)-piperazin-1-yl and homopiperazin-1-yl.

Suitably, the cyclic moiety —NR^(b)R^(c) may be substituted by C₁₋₆alkyl, especially methyl. Particular values of —NR^(b)R^(c) includepyrrolidin-1-yl, morpholin-4-yl and 4-methylpiperazin-1-yl.

Typically, R³ represents cyano, —CO₂R^(a), —CONR^(b)R^(c), or—CON(OR^(b))R^(c), in which R^(a), R^(b) and R^(c) are as defined above.Suitably, R³ represents cyano, —CO₂R^(a) or —CONR^(b)R^(c), especiallycyano or —CONR^(b)R^(c), in which R^(a), R^(b) and R^(c) are as definedabove. Suitably, R³ represents —CON(OR^(b))R^(c), in which R^(b) andR^(c) are as defined above.

In one embodiment, R³ represents cyano. In another embodiment, R³represents —CO₂R^(a), in which R^(a) is as defined above. In a furtherembodiment, R³ represents —CONR^(b)R^(c), in which R^(b) and R^(c) areas defined above. In an additional embodiment, R³ represents—CON(OR^(b))R^(c), in which R^(b) and R^(c) are as defined above. In astill further embodiment, R³ represents hydrogen.

A particular sub-group of compounds according to the invention isrepresented by the compounds of formula (II), and pharmaceuticallyacceptable salts, solvates and N-oxides thereof:

wherein

R¹² represents halogen; and

R³ is as defined above.

In one specific embodiment, R¹² is bromo. In another specificembodiment, R¹² is iodo.

Specific novel compounds in accordance with the present inventioninclude each of the compounds whose preparation is described in theaccompanying Examples, and pharmaceutically acceptable salts andsolvates thereof.

The present invention also provides a pharmaceutical composition whichcomprises a compound of formula (I) as defined above, or apharmaceutically acceptable salt, solvate or N-oxide thereof, inassociation with one or more pharmaceutically acceptable carriers.

Pharmaceutical compositions according to the invention may take a formsuitable for oral, buccal, parenteral, nasal, topical, ophthalmic orrectal administration, or a form suitable for administration byinhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methyl cellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogenphosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles or preservatives. Thepreparations may also contain buffer salts, flavouring agents, colouringagents or sweetening agents, as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of formula (I) may be formulated for parenteraladministration by injection, e.g. by bolus injection or infusion.Formulations for injection may be presented in unit dosage form, e.g. inglass ampoules or multi-dose containers, e.g. glass vials. Thecompositions for injection may take such forms as suspensions, solutionsor emulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilising, preserving and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

In addition to the formulations described above, the compounds offormula (I) may also be formulated as a depot preparation. Suchlong-acting formulations may be administered by implantation or byintramuscular injection.

For nasal administration or administration by inhalation, the compoundsaccording to the present invention may be conveniently delivered in theform of an aerosol spray presentation for pressurised packs or anebuliser, with the use of a suitable propellant, e.g.dichlorodifluoromethane, fluorotrichloromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack or dispensing device may be accompanied byinstructions for administration.

For topical administration the compounds according to the presentinvention may be conveniently formulated in a suitable ointmentcontaining the active component suspended or dissolved in one or morepharmaceutically acceptable carriers. Particular carriers include, forexample, mineral oil, liquid petroleum, propylene glycol,polyoxyethylene, polyoxypropylene, emulsifying wax and water.Alternatively, the compounds according to the present invention may beformulated in a suitable lotion containing the active componentsuspended or dissolved in one or more pharmaceutically acceptablecarriers. Particular carriers include, for example, mineral oil,sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearylalcohol, benzyl alcohol, 2-octyldodecanol and water.

For ophthalmic administration the compounds according to the presentinvention may be conveniently formulated as microionized suspensions inisotonic, pH-adjusted sterile saline, either with or without apreservative such as a bactericidal or fungicidal agent, for examplephenylmercuric nitrate, benzylalkonium chloride or chlorhexidineacetate. Alternatively, for ophthalmic administration compounds may beformulated in an ointment such as petrolatum.

For rectal administration the compounds according to the presentinvention may be conveniently formulated as suppositories. These can beprepared by mixing the active component with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and so will melt in the rectum to release the activecomponent. Such materials include, for example, cocoa butter, beeswaxand polyethylene glycols.

The quantity of a compound of the invention required for the prophylaxisor treatment of a particular condition will vary depending on thecompound chosen and the condition of the patient to be treated. Ingeneral, however, daily dosages may range from around 10 ng/kg to 1000mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to40 mg/kg body weight, for oral or buccal administration, from around 10ng/kg to 50 mg/kg body weight for parenteral administration, and fromaround 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000mg, for nasal administration or administration by inhalation orinsufflation.

The compounds of formula (I) above, and the N-oxides thereof, may beprepared by a process which comprises reacting a compound of formula(III), or an N-oxide thereof, with a compound of formula (IV):

wherein R¹, R² and R³ are as defined above, and L¹ represents a suitableleaving group.

The leaving group L¹ is typically a halogen atom, e.g. chloro.

The reaction is conveniently effected, at an elevated temperature ifnecessary, in a suitable solvent, e.g. dimethylsulphoxide, typicallyunder basic conditions, e.g. in the presence of an inorganic base suchas sodium hydride.

The intermediates of formula (IV) above may be prepared by reacting acompound of formula (V):

wherein R¹ and R² are as defined above; with thiophosgene.

The reaction is conveniently effected in a suitable solvent, typically amixture of chloroform and water.

In another procedure, the compounds of formula (I) above wherein R³represents

—CONR^(b)R^(c) or —CON(OR^(b))R^(c), and the N-oxides thereof, may beprepared by a process which comprises reacting a compound of formulaH—NR^(b)R^(c) or H—N(OR^(b))R^(c) with a compound of formula (VI), or anN-oxide thereof:

wherein R¹, R², R^(b) and R^(c) are as defined above; in the presence ofa condensing agent.

A suitable condensing agent is 1-(3-dimethylaminopropyl)-3-carbodiimidehydrochloride (EDC), in which case the reaction is conveniently effectedin the presence of 1-hydroxybenzotriazole (HOBT) and N-methylmorpholine(NMM).

The compounds of formula (VI) above may be prepared by reacting thecompound of formula (VII):

with a compound of formula (V) as defined above.

The reaction may conveniently be effected by treating compound (V) witha base, e.g. lithium bis(trimethylsilyl)amide, in a suitable solvent,e.g. tetrahydrofuran, followed by the addition of compound (VII).

The intermediate of formula (VII) above may be prepared from a compoundof formula (VIII):

wherein R^(a) is as defined above; by saponification of the ester moietyfollowed by oxidation of the methylsulfanyl group.

Saponification of the ester moiety —CO₂R^(a) in compound (VIII) may beeffected by treatment with an alkaline base, e.g. sodium hydroxide, in asuitable solvent, e.g. an aqueous mixture of a lower alkanol such asmethanol and a cyclic ether such as tetrahydrofuran. Oxidation of themethylsulfanyl group in the resulting compound may then be effected bytreatment with a suitable oxidising agent, e.g. Oxone® (potassiumperoxymonosulfate), in an appropriate solvent, e.g. aqueous methanol.

The intermediates of formula (VIII) above may be prepared by reacting acompound of formula (III), wherein R³ is —CO₂R^(a) as defined above,with carbon disulfide, followed by treatment with a methyl halide suchas iodomethane.

The reaction is conveniently effected in a suitable solvent, e.g.dimethylsulfoxide, in the presence of a base such as sodium hydride.

Where they are not commercially available, the starting materials offormula (III) and (V) may be prepared by methods analogous to thosedescribed in the accompanying Examples, or by standard methods wellknown from the art.

It will be understood that any compound of formula (I) initiallyobtained from any of the above processes may, where appropriate,subsequently be elaborated into a further compound of formula (I) bytechniques known from the art. By way of example, a compound of formula(I) wherein R³ represents —CO₂R^(a) may be converted into thecorresponding compound wherein R³ represents —CONH₂ by treatment withammonia, typically in a lower alkanol solvent, e.g. ethanol, at elevatedtemperature and pressure. Alternatively, a compound of formula (I)wherein R³ represents —CO₂R^(a) may be converted into the correspondingcompound wherein R³ represents —CONR^(b)R^(c) by treatment with theappropriate amine of formula H—NR^(b)R^(c) in the presence oftrimethylaluminium. A compound of formula (I) wherein R³ represents—CO₂R^(a) may be converted into the corresponding compound wherein R³represents hydrogen by treatment with an alkaline reagent such aslithium hydroxide under forcing conditions, e.g. by heating at reflux ina mixture of ethanol and water. A compound of formula (I) wherein R³contains a 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl moiety may be convertedinto the corresponding compound wherein R³ contains a2,3-dihydroxypropyl moiety by treatment with a mineral acid such ashydrochloric acid. A compound of formula (I) wherein R³ contains anitrogen atom to which a tert-butoxycarbonyl (BOC) group is attached maybe converted into the corresponding compound wherein R³ contains an N—Hfunctionality by treatment with an acid, e.g. a mineral acid such ashydrochloric acid, or an organic acid such as trifluoroacetic acid. Acompound of formula (I) wherein R³ contains an N—H functionality may beconverted into the corresponding compound wherein R³ contains a nitrogenatom to which an ethoxycarbonylmethyl group is attached by treatmentwith ethyl chloroacetate, typically in the presence of triethylamine;the resulting compound may then be converted into the correspondingcompound wherein R³ contains a nitrogen atom to which a carboxymethylgroup is attached by treatment with an alkaline reagent such as sodiumhydroxide, typically in an aqueous solution of a lower alkanol such asethanol. The pyridine-N-oxide derivative of a compound of formula (I)may be converted into the corresponding compound of formula (I) bytreatment with triphenyl phosphine and phosphorus trichloride.

Where a mixture of products is obtained from any of the processesdescribed above for the preparation of compounds according to theinvention, the desired product can be separated therefrom at anappropriate stage by conventional methods such as preparative HPLC; orcolumn chromatography utilising, for example, silica and/or alumina inconjunction with an appropriate solvent system.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques. In particular,where it is desired to obtain a particular enantiomer of a compound offormula (I) this may be produced from a corresponding mixture ofenantiomers using any suitable conventional procedure for resolvingenantiomers. Thus, for example, diastereomeric derivatives, e.g. salts,may be produced by reaction of a mixture of enantiomers of formula (I),e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base.The diastereomers may then be separated by any convenient means, forexample by crystallisation, and the desired enantiomer recovered, e.g.by treatment with an acid in the instance where the diastereomer is asalt. In another resolution process a racemate of formula (I) may beseparated using chiral HPLC. Moreover, if desired, a particularenantiomer may be obtained by using an appropriate chiral intermediatein one of the processes described above. Alternatively, a particularenantiomer may be obtained by performing an enantiomer-specificenzymatic biotransformation, e.g. an ester hydrolysis using an esterase,and then purifying only the enantiomerically pure hydrolysed acid fromthe unreacted ester antipode. Chromatography, recrystallisation andother conventional separation procedures may also be used withintermediates or final products where it is desired to obtain aparticular geometric isomer of the invention.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 3^(rd) edition, 1999. The protecting groups may be removedat any convenient subsequent stage utilising methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

The compounds in accordance with this invention potently inhibit theactivity of human MEK enzyme.

In Vitro MEK Assay

MEK1 activity was measured in a cascade assay initiated by active Raf,via activation of MEK, Erk2 and subsequent phosphorylation offluorescein-labelled Erk-tide substrate in an assay based onfluorescence polarisation (IMAP). The assay was carried out in 20 mMTris+5 mM MgCl₂+2 mM DL-dithiothreitol+0.01% Tween 20 pH 7.2, containing1.5 nM unactive MEK, 100 nM unactive Erk and 200 nM Erk-tide (allconcentrations are final concentrations). Compounds, or DMSO controls,were tested at a final concentration of 2% DMSO, and the assay initiatedin the presence of 5 μM ATP by addition of 1.25 nM active Raf in assaybuffer. After 20 min at r.t., stop solution was added followed by IMAPbinding beads, the assay mixture was then incubated for 90 min at r.t.(with shaking) and then read on a Molecular Devices UL HT reader.

When tested in the above assay, the compounds of the accompanyingExamples were all found to inhibit human MEK enzyme with IC₅₀ values of10 μM or better.

EXAMPLES Abbreviations Used

-   EtOAc—ethyl acetate DMSO—dimethylsulphoxide-   THF—tetrahydrofuran DCM—dichloromethane-   ether—diethyl ether CDCl₃—deuterochloroform-   MeOH—methanol MeCN—acetonitrile-   EtOH—ethanol ES—electrospray-   DMF—N,N-dimethylformamide HOBT—1-hydroxybenzotriazole-   SiO₂—silica NMM—N-methylmorpholine-   h—hour(s) min—minute(s)-   r.t.—room temperature aq—aqueous sat.—saturated RT—retention time-   BOC—tert-butoxycarbonyl LiHMDS—lithium bis(trimethylsilyl)amide-   MCPBA—3-chloroperoxybenzoic acid-   EDC—1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride

All NMR spectra were obtained either at 300 MHz or 400 MHz.

Compounds were named with the aid of ACD Labs Name (v. 7.0) supplied byAdvanced Chemical Development, Toronto, Canada.

Standard LCMS Method

The LC-MS system used comprises a Waters Alliance 2795 HT quaternaryHPLC, Waters 996 Photo Diode Array (PDA) detector and Waters ZQ 4000single quadrupole mass spectrometer. The ZQ can acquire datasimultaneously in positive and negative electrospray ionisation modes.

ZQ Mass Spectrometer Capillary 3.5 kV Cone 50 V Extractor 2 V SourceTemp 80° C. Desolvation Temp 200° C. Cone Gas 150 L/h Desolvation Gas250 L/h Multiplier 650 V [000108]Data were acquired in a full scan from100 to 1000 m/z. Scan duration 0.80 s Interscan delay 0.20 s

HPLC

Analytical reverse phase separation was carried out on a Gemini C18 fromPhenomenex 50×4.6 mm with 5 μm silica.

Injection 5 μL Volume UV data 240 to 400 nm Sample 20° C. TemperatureColumn 30° C. Temperature Flow Rate 0.9 mL/min Split to ZQ ~0.40 mL/minSolvent A: 90% 10 mM NH₄CO₂ in water/0.1% formic acid/10% CH₃CNSolvent B: 90% CH₃CN/0.1% formic acid/10% 10 mM NH₄CO₂ in waterSolvent C: 90% 10 mM NH₄CO₂ in water/0.1% ammonia/10% CH₃CNSolvent D: 90% CH₃CN/10% 10 mM NH₄CO₂ in water/0.1% ammonia

Gradient Program

For Method 5_(—)95_pH=3

Time (min) A % B % Flow Curve 0.00 95.0 5.0 0.900 1 2.00 5.0 95.0 0.9006 4.00 5.0 95.0 0.900 6 5.00 95.0 5.0 0.900 6For Method 5_(—)95_pH=10

Time (min) A % B % Flow Curve 0.00 95.0 5.0 0.900 1 2.00 5.0 95.0 0.9006 4.00 5.0 95.0 0.900 6 5.00 95.0 5.0 0.900 6

Preparative UV-HPLC

The LC system comprises a Waters 2525 quaternary pump, a Waters 996Photo Diode Array (PDA) detector, a Waters 2700 sample manager, a ColumnFluidics Organiser and a Waters Fraction Collector operating in reversephase at one of two pH systems.

Low pH System (Approximately pH 3.2)

The reverse phase separation was carried out on a Luna C18 fromPhenomenex 100×21.2 mm with 5 μm silica.

Injection Volume 500 μL UV data 254 nm Flow Rate 20 mL/minSolvent A 90% water/10% CH3CN/0.1% formic acidSolvent B 90% CH3CN/10% water/0.1% formic acid

High pH System (Approximately pH 9.5)

The reverse phase separation was carried out on a Gemini C18 fromPhenomenex 150×21.2 mm with 10 μm silica.

Injection Volume 500 μL UV data 254 nm Flow Rate 20 mL/minSolvent C 90% 10 mM NH₄HCO₂ in water/0.1% Ammonia/10% CH₃CNSolvent D 90% CH₃CN/10% 10 mM NH₄HCO₂ in water/0.1% Ammonia

Typical gradient profiles are described below:

Gradient Program for Low pH Method

Time A % B % C % D % Flow Curve 0.00 95.0 5.0 0.0 0.0 20 1 9.00 5.0 95.00.0 0.0 20 6 11.00 5.0 95.0 0.0 0.0 20 6 11.50 95.0 5.0 0.0 0.0 20 612.00 95.0 5.0 0.0 0.0 20 6

Gradient Program for High pH Method

Time A % B % C % D % Flow Curve 0.00 0.0 0.0 95.0 5.0 20 1 9.00 0.0 0.05.0 95.0 20 6 11.00 0.0 0.0 5.0 95.0 20 6 11.50 0.0 0.0 95.0 5.0 20 612.00 0.0 0.0 95.0 5.0 20 6

Intermediate 1 2-Fluoro-4-iodo-1-isothiocyanatobenzene

Thiophosgene (3.55 mL, 46.4 mmol) was added to a rapidly-stirred mixtureof 2-fluoro-4-iodoaniline (10.0 g, 42.2 mmol) in CHCl₃ (200 mL) andwater (100 mL). The mixture was stirred at r.t. for 16 h. The organicphase was dried (Na₂SO₄) and concentrated in vacuo to give the titlecompound as an off-white crystalline solid (11.8 g, quant.). δ_(H)(DMSO-d₆) 7.87 (1H, dd, J 1.8, 9.5 Hz), 7.63 (1H, ddd, J 1.0, 1.8, 8.4Hz), 7.25 (1H, dd, J 8.2, 8.4 Hz).

Intermediate 2 Ethyl2-[(4-bromo-2-fluorophenyl)amino]thieno[2,3-b]pyridine-3-carboxylate

Prepared from ethyl (2-chloropyridin-3-yl)acetate (D. H. Bremner et al.,Synthesis, 1997, 949) (500 mg, 2.5 mmol) and 4-bromo-2-fluorophenylisothiocyanate (580 mg, 2.5 mmol) by the method of Example 1. Titlecompound obtained as an off-white solid (390 mg, 40%). δ_(H) (DMSO-d₆)10.37 (1H, br s), 8.25 (1H, dd, J 1.4, 8.1 Hz), 8.19 (1H, d, J 4.8 Hz),7.69 (1H, dd, J 1.8, 10.2 Hz), 7.56-7.45 (2H, m), 7.32 (1H, dd, J 4.5,8.1 Hz), 4.35 (2H, q, J 7.1 Hz), 1.37 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT4.66 minutes, 395 (M(⁷⁹Br)+H)⁺.

Intermediate 3 3-(tert-Butyldimethylsilanyloxy)propylamine

To a solution of N-(3-hydroxypropyl)phthalimide (5.25 g, 24.36 mmol) inDMF (20 mL) was added imidazole (16.6 g, 240 mmol) andtert-butyldimethylsilyl chloride (19 g, 120 mmol). The reaction wasstirred at room temperature for 18 hours before the volatiles wereremoved in vacuo and a portion of the crude product was subjected tocolumn chromatography (SiO₂, 1:1 DCM/hexanes) to give2-[3-(tert-butyldimethylsilanyloxy)propyl]isoindole-1,3-dione as a clearoil (5 g). 2-[3-(tert-Butyldimethylsilanyloxy)propyl]isoindole-1,3-dione(5 g, 26.4 mmol) was dissolved in ethanol (50 ml) and methyl hydrazine(2.94 ml, 55.4 mmol) added. The reaction was heated to 75° C. for 8hours before concentration in vacuo. The crude residue was trituratedwith a mixture of diethyl ether (150 mL) and hexanes (50 mL) and theresultant solid removed by filtration. The solvents were removed invacuo to give the title compound as a pale yellow oil (1.8 g, 61%).δ_(H) (DMSO-d₆) 4.58 (2H, br s), 3.63-3.58 (2H, m), 2.67-2.62 (2H, m),1.60-1.55 (2H, m), 0.83 (9H, d, J 1.1 Hz), 0.00 (6H, d, J 1.2 Hz). LCMS(ES⁺) RT 1.77 minutes, 190 (M+H)⁺.

Intermediate 4 2-Methylsulfanylthieno[2,3-b]pyridine-3-carboxylic AcidEthyl Ester

To a solution of ethyl (2-chloropyridin-3-yl)acetate (D. H. Bremner etal., Synthesis, 1997, 949) (8.0 g, 40.0 mmol) and carbon disulfide (3.18g, 42.0 mmol) in DMSO (100 mL) was added sodium hydride portionwise (2.4g, 60.0 mmol). After 60 minutes stirring at room temperature the mixturewas heated at 80° C. for 2 hours. After this time the reaction mixturewas allowed to cool to room temperature and methyl iodide (7.6 g, 54.0mmol) added. After 18 hours ice (50 mL) was added and a yellowprecipitate formed which was isolated via filtration to give the titlecompound as a grey solid (7.95 g, 78%). δ_(H) (DMSO-d₆) 8.60 (1H, dd, J1.6, 8.2 Hz), 8.46, (1H, dd, J 1.6, 4.6 Hz), 7.35 (1H, dd, J 4.6, 8.2Hz), 4.48 (2H, q, J 7.1 Hz), 2.71, (3H, s), 1.49 (3H, t, J 7.1 Hz).

Intermediate 5 2-Methylsulfanylthieno[2,3-b]pyridine-3-carboxylic Acid

A mixture of Intermediate 4 (12.5 g, 50.0 mmol) in THF (200 mL) and MeOH(50 mL) was treated with sodium hydroxide solution (10% solution inwater, 50 mL) and stirred at room temperature for 18 h. After this timethe reaction mixture was reduced in vacuo to one third of its volume.Water (50 mL) was then added before 10% HCl was added until a whiteprecipitate formed. This was filtered to give the title compound as acrystalline white solid (10.6 g, 95%). δ_(H) (DMSO-d₆) 13.50-13.20 (1Hbr s), 8.55 (1H, dd, J 1.2, 8.2 Hz), 8.48 (1H, dd, J 1.3, 4.5 Hz), 7.49(1H, dd, J 4.6, 8.2 Hz), 3.25 (3H, s).

Intermediate 6 2-Methanesulfinylthieno[2,3-b]pyridine-3-carboxylic Acid

Oxone (14.5 g, 24.0 mmol) dissolved in water (25 mL) was added to arapidly stirred mixture of Intermediate 5 (10.6 g, 47 mmol) in MeOH (250mL). The mixture was stirred at room temperature for 4 h. The reactionmixture was separated between DCM (300 mL) and water (200 mL). Theorganic layer was dried (Na₂SO₄) and concentrated in vacuo to give thetitle compound as a white crystalline solid (10.0 g, 88%). δ_(H)(DMSO-d₆) 14.20-13.80 (1H, br s), 8.73 (1H, dd, J 1.7, 8.3 Hz), 8.69(1H, J 1.7, 4.6 Hz), 7.61 (1H, dd, J 4.6, 8.3 Hz), 3.05 (3H, s).

Intermediate 72-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic Acid

To a stirred solution of 2-fluoro-4-iodoaniline (6.0 g, 25 mmol) in THF(100 mL) at 0° C. (ice bath) was added LiHMDS (1.0 M solution in THF,20.0 mL, 20.0 mmol) slowly. The mixture was allowed to stir at roomtemperature for 30 minutes before cooling to 0° C. and Intermediate 6(2.0 g, 8.3 mmol) was added portionwise. The mixture was stirred at roomtemperature for 1 hour. After this time the reaction mixture was pouredonto ice and when at ambient temperature citric acid was added until aprecipitate formed. The mixture was filtered to give the title compoundas a pale brown crystalline solid (2.9 g, 84%). δ_(H) (DMSO-d₆)14.00-13.00 (1H, br s), 10.80 (1H, s), 8.36 (1H, dd, J 1.3, 8.1 Hz),8.32 (1H, dd, J, 1.3, 4.8 Hz), 7.84 (1H, dd, J 1.8, 10.1 Hz), 7.69 (1H,d, J 8.3 Hz), 7.54 (1H, m), 7.42 (1H, dd, J 8.3, 4.8 Hz).

Intermediate 8 4-Iodo-1-isothiocyanato-2-methylbenzene

To a stirring solution of 4-iodo-2-methylaniline (1.0 g, 4.2 mmol) inDCM (50 mL) was added water (20 mL) followed by thiophosgene (490 mg,4.2 mmol). The reaction mixture was stirred overnight before the layerswere separated and the organic layer dried (Na₂SO₄) and evaporated invacuo to give the desired product as a brown solid (1.05 g, 89%). δ_(H)(CDCl₃) 7.75 (1H, d, J 1.2 Hz), 7.62 (1H, dd, J 1.2, 8.3 Hz), 7.15 (1H,d, J 8.3 Hz), 2.20 (3H, s).

Intermediate 9 2-Chloro-4-iodo-1-isothiocyanatobenzene

To a stirred solution of 2-chloro-4-iodoaniline (1.0 g, 3.9 mmol) in DCM(50 mL) was added water (20 mL) followed by thiophosgene (476 mg, 4.1mmol). The reaction mixture was stirred overnight before the layers wereseparated and the organic layer dried (Na₂SO₄) and evaporated in vacuoto give the desired product as a brown solid (1.0 g, 86%). δ_(H) (CDCl₃)7.79 (1H, d, J 1.9 Hz), 7.58 (1H, dd, J 1.9, 8.4 Hz), 6.97 (1H, d, J 8.4Hz).

Intermediate 10(2R)-2-[({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}amino)-methyl]pyrrolidine-1-carboxylicAcid Tert-Butyl Ester

1-(3-Dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) was added to a solution of Intermediate 7 (150 mg, 0.36 mmol),1-hydroxybenzotriazole (98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL,0.99 mmol) and (R)-2-(aminomethyl)-1-BOC-pyrrolidine (144 mg, 0.72 mmol)in N,N-dimethylformamide (5 mL). The reaction mixture was stirred atr.t. for 20 h, then poured into EtOAc (25 mL). The organic solution waswashed with sat. brine (3×25 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo to give a brown solid. The crude product wassubjected to column chromatography (SiO₂, 4:1 hexanes/EtOAc) to give thetitle compound, which was evaporated from ether to give a hard foam (135mg, 63%). OH (CDCl₃) 11.67 (1H, s), 8.35-8.33 (2H, m), 8.04 (1H, br s),7.54-7.43 (3H, m), 7.32-7.30 (1H, m), 4.19 (1H, m), 3.82-3.78 (1H, m),3.53-3.35 (3H, m), 2.18-1.86 (3H, m), 1.78 (1H, m), 1.45 (9H, s).

Intermediate 11(2S)-2-[({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}amino)-methyl]pyrrolidine-1-carboxylicAcid Tert-Butyl Ester

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and (S)-2-(aminomethyl)-1-BOC-pyrrolidine (144 mg, 0.72 mmol) bythe method of Intermediate 10. The title compound was evaporated fromether to give a colourless hard foam (139 mg, 64%). δ_(H) (CDCl₃) 11.67(1H, s), 8.35-8.33 (2H, m), 8.04 (1H, br s), 7.54-7.43 (3H, m),7.32-7.30 (1H, m), 4.19 (1H, m), 3.82-3.78 (1H, m), 3.53-3.35 (3H, m),2.18-1.86 (3H, m), 1.78 (1H, m), 1.45 (9H, s).

Intermediate 12 (2-Chloropyridin-3-yl)acetic Acid

2-Chloro-3-(cyanomethyl)pyridine (D. H. Bremner et al., Synthesis, 1997,949) (10.3 g, 67.1 mmol) in conc. HCT (100 mL) was heated at reflux for3 h. The reaction mixture was concentrated in vacuo and the residuesuspended in water. The white solid was collected by filtration andwashed with water, then dried in vacuo yielding the required product(11.15 g). δ_(H) (DMSO-d₆) 12.60 (1H, br s), 8.32 (1H, dd, J 4.7, 1.9Hz), 7.86 (1H, dd, J 7.5, 1.9 Hz), 7.40 (1H, dd, J 7.5, 4.7 Hz), 3.75(2H, s). LCMS (ES⁺) RT 1.85 minutes, 174 (M+H)⁺.

Intermediate 13 (2-Chloropyridin-3-yl)acetic Acid Methyl Ester

To a suspension of Intermediate 12 (3.88 g, 22.6 mmol) in methanol wasadded acetyl chloride (1.8 mL, 24.9 mmol) and the mixture heated at 70°C. for 18 hours. The solvents were removed in vacuo to give the titlecompound as a pale brown oil (4.63 g, quant). δ_(H) (DMSO-d₆) 8.35 (1H,dd, J 4.7, 1.9 Hz), 7.88 (1H, dd, J 8.5, 1.9 Hz), 7.43 (1H, dd, J 8.5,4.7 Hz), 3.80 (2H, s), 3.65 (3H, s). LCMS (ES⁺) RT 2.40 minutes, 186(M+H)⁺.

Intermediate 142-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic AcidMethyl Ester

To a solution of Intermediate 13 (4.1 g, 22.1 mmol) and Intermediate 1(6.16 g, 22.1 mmol) in dry DMSO under nitrogen was added sodium hydride(1.05 g, 24.3 mmol, 60 wt % dispersion in mineral oil). The mixture wasstirred at room temperature for 15 minutes then heated to 90° C. for 3hours. The reaction was cooled, then poured onto iced water (200 mL).The aqueous phase was extracted with EtOAc (3×200 mL), the combinedorganics washed with brine, dried (MgSO₄), filtered and the solventsremoved in vacuo. The sticky yellow solid was triturated with ethanol togive a fine yellow solid which was collected by filtration, washed withdiethyl ether and dried under suction to give the title compound as apale yellow solid (1.73 g). δ_(H) (DMSO-d₆) 10.30 (1H, s), 8.36-8.31(2H, m), 7.87 (1H, dd, J 1.9, 10.0 Hz), 7.70 (1H, d, J 6.6 Hz), 7.51(1H, t, J 8.5 Hz), 7.42 (1H, dd, J 5.7, 8.1 Hz), 3.94 (3H, s). LCMS(ES⁺) RT 4.00 minutes, 429 (M+H)⁺.

Intermediate 15 2-(2-Chloropyridin-3-yl)-N-methoxy-N-methylacetamide

Intermediate 12 (500 mg, 2.9 mmol) in dichloromethane (20 mL) with N,O-dimethylhydroxylamine (300 mg, 3.04 mmol), EDC (583 mg, 3.04 mmol) andN-methylmorpholine (0.98 mL, 8.70 mmol) were stirred at r.t. for 18 h.The reaction mixture was washed with 2M HCl, and the organic phase wasdried (magnesium sulphate) and concentrated in vacuo. Chromatography(SiO₂; 1:1 ethyl acetate:DCM) yielded the title compound (320 mg) as awhite solid. δ_(H) (DMSO-d₆) 8.31 (1H, dd, J 4.7, 1.9 Hz), 7.81 (1H, dd,J 7.5, 1.9 Hz), 7.40 (1H, dd, J 7.5, 4.7 Hz), 3.93 (2H, s), 3.76 (3H,s), 3.15 (3H, s). LCMS (ES⁺) RT 2.22 minutes, 215/217 (M+H)⁺.

Intermediate 162-(2-Chloro-1-oxypyridin-3-yl)-N-methoxy-N-methylacetamide

Intermediate 15 (270 mg, 1.25 mmol) was dissolved in DCM (5 mL) andtreated with mCPBA (324 mg, 1.88 mmol). After stirring at r.t. for 3days the reaction mixture was poured directly onto a flash column andchromatographed (SiO₂; ethyl acetate→5% methanol in ethyl acetate),yielding the required product (265 mg) as a white solid. δ_(H) (DMSO-d₆)8.39 (1H, dd, J 5.4, 2.5 Hz), 7.37-7.35 (2H, m), 3.98 (2H, s), 3.76 (3H,s), 3.15 (3H, s). LCMS (ES⁺) RT 1.81 minutes, 231/233 (M+H)⁺.

Example 1 Ethyl2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylate

Sodium hydride (650 mg of a 60% dispersion in mineral oil, 16.2 mmol)was added portionwise over 10 min to a mixture of Intermediate 1 (3.75g, 13.5 mmol) and ethyl (2-chloropyridin-3-yl)acetate (D. H. Bremner etal., Synthesis, 1997, 949) (2.7 g, 13.5 mmol) in DMSO (25 mL). When gasevolution had slowed the mixture was heated at 70° C. for 3 h then leftat r.t. overnight. Water (150 mL) was added and the liquid decanted offfrom the resulting solid. The solid mass was treated with ethanol (40mL) to give a fine white suspension which was filtered off, washed withethanol (10 mL) and ether (2×15 mL) and dried in vacuo at 40° C. to givethe title compound as a white solid (2.90 g, 48%). δ_(H) (DMSO-d₆) 10.40(1H, s), 8.40-8.30 (2H, m), 7.85 (1H, dd, J 1.9, 10.1 Hz), 7.70 (1H, d,J 8.5 Hz), 7.55-7.49 (1H, m), 7.43 (1H, dd, J 4.9, 8.0 Hz), 4.43 (2H, q,J 7.9 Hz), 1.41 (3H, t, J 7.9 Hz). LCMS (ES⁺) RT 5.27 minutes, 443(M+H)⁺.

Example 22-[(2-Fluoro-4-iodophenyl)amino]-N-methylthieno[2,3-b]pyridine-3-carboxamide

Trimethylaluminium (1.5 mL of a 2M solution in hexane, 3.0 mmol) wasadded to a solution of methylamine (1.5 mL of a 2M solution in THF, 3.0mmol) in toluene (5 mL). After 5 min Example 1 (250 mg, 0.60 mmol) wasadded and the mixture heated at 100° C. for 4 h. After cooling thereaction was quenched with sat. ammonium chloride solution (75 mL) andHCl (10 mL, 2M) then extracted with EtOAc (80 mL). The organic phase wasdried (Na₂SO₄) and concentrated in vacuo to give a solid. Triturationwith ether (30 mL) and filtration gave the title compound as anoff-white solid (138 mg, 57%). δ_(H) (CDCl₃) 11.13 (1H, br s), 8.25 (1H,dd, J 1.4, 4.7 Hz), 7.80 (1H, dd, J 1.4, 8.2 Hz), 7.46-7.42 (2H, m),7.33 (1H, dd, J 8.3, 8.3 Hz), 7.21 (1H, dd, J 4.7, 8.2 Hz), 5.82 (1H, brs), 3.00 (3H, d, J 4.8 Hz). LCMS (ES⁻) RT 3.63 minutes, 426 (M−H)⁻.

Example 32-[(2-Fluoro-4-iodophenyl)amino]-N,N-dimethylthieno[2,3-b]pyridine-3-carboxamide

Prepared from Example 1 (100 mg, 0.23 mmol) and dimethylamine (0.35 mLof 2.0M solution in THF, 0.7 mmol) by the method of Example 2. Titlecompound obtained as a white solid (21 mg, 20%). δ_(H) (DMSO-d₆) 9.12(1H, s), 8.35 (1H, dd, J 1.6, 4.7 Hz), 7.77 (1H, dd, J 1.6, 8.1 Hz),7.67 (1H, dd, J 1.9, 10.6 Hz), 7.48 (1H, dd, J 1.1, 1.9 Hz), 7.35 (1H,dd, J 4.7, 8.0 Hz), 7.15-7.10 (1H, m), 2.87 (6H, s). LCMS (ES⁺) RT 3.29minutes, 442 (M+H)⁺.

Example 4N-(2-Fluoro-4-iodophenyl)-3-(morpholin-4-ylcarbonyl)thieno[2,3-b]pyridin-2-amine

Prepared from Example 1 (250 mg, 0.60 mmol) and morpholine (0.26 mL, 3mmol) by the method of Example 2. Title compound obtained as a whitesolid (215 mg, 78%). δ_(H) (DMSO-d₆) 9.22 (1H, br s), 8.34 (1H, dd, J1.4, 4.6 Hz), 7.81 (1H, dd, J 1.4, 8.0 Hz), 7.68 (1H, dd, J 1.9, 10.5Hz), 7.50-7.46 (1H, m), 7.35 (1H, dd, J 4.6, 8.0 Hz), 7.13 (1H, dd, J8.6, 8.6 Hz), 3.54-3.48 (4H, m), 3.43-3.39 (4H, m). LCMS (ES⁺) RT 3.17minutes, 484 (M+H)⁺.

Example 5N-(2-Fluoro-4-iodophenyl)-3-[(4-methylpiperazin-1-yl)carbonyl]thieno[2,3-b]pyridin-2-amine

Trimethylaluminium (1.5 mL of a 2M solution in hexane, 3.0 mmol) wasadded to a solution of 1-methylpiperazine (0.333 mL, 3.0 mmol) intoluene (5 mL). After 10 min Example 1 (250 mg, 0.60 mmol) and toluene(2 mL) were added and the mixture heated at 90° C. for 6 h. Aftercooling the mixture was quenched with NaOH (50 mL, 1M) and extractedwith EtOAc (50 mL plus 25 mL). The combined organic extracts were washedwith sat. brine (50 mL), dried (Na₂SO₄) and concentrated in vacuo togive a yellow solid. Trituration with hexane/ether (10:1, 30 mL) andfiltration gave the title compound as a pale yellow solid (245 mg, 87%).δ_(H) (DMSO-d₆) 9.13 (1H, br s), 8.37 (1H, br d, J 4.4 Hz), 7.79 (1H, brd, J 7.8 Hz), 7.67 (1H, br d, J 10.4 Hz), 7.47 (1H, br d, J 8.4 Hz),7.37 (1H, dd, J 4.7, 8.1 Hz), 7.10 (1H, m), 3.30 (4H, br s), 2.21 (4H,br s), 2.14 (3H, s). LCMS (ES⁺) RT 2.09 minutes, 497 (M+H)⁺.

Example 62-[(4-Bromo-2-fluorophenyl)amino]-N-(2,3-dihydroxypropyl)thieno[2,3-b]pyridine-3-carboxamide

Trimethylaluminium (0.95 mL of a 2M solution in hexane, 1.90 mmol) wasadded to a solution of 2,2-dimethyl-1,3-dioxolane-4-methanamine (249 mg,1.9 mmol) in toluene (4 mL). After 2 minutes Intermediate 2 (150 mg,0.38 mmol) was added and the mixture heated at 90° C. for 4 h. Aftercooling the reaction was quenched with sat. ammonium chloride solution(5 mL) and HCl (5 mL, 2M), stirred, then extracted with EtOAc (2×25 mL)and DCM (25 mL). The organic phase was dried (Na₂SO₄) and concentratedin vacuo to give a solid. Trituration with ether/hexane (1:3, 10 mL) andfiltration gave the title compound as a white solid (95 mg, 57%). δ_(H)(DMSO-d₆) 10.64 (1H, br s), 8.36 (1H, dd, J 1.4, 4.7 Hz), 8.20 (1H, dd,J 1.4, 8.2 Hz), 7.89 (1H, dd, J 8.8, 8.8 Hz), 7.69 (1H, dd, J 2.1, 10.6Hz), 7.58 (1H, dd, J 8.8, 8.8 Hz), 7.48-7.41 (2H, m), 4.86 (1H, d, J 5.0Hz), 4.64 (1H, t, J 5.7 Hz), 3.72-3.66 (1H, m), 3.52-3.36 (3H, m),3.31-3.22 (1H, m). LCMS (ES⁺) RT 2.80 minutes, 440 (M(⁷⁹Br)+H)⁺.

Example 72-[(2-Fluoro-4-iodophenyl)amino]-N-(2,3-dihydroxypropyl)thieno[2,3-b]pyridine-3-carboxamide

Prepared from Example 1 (150 mg, 0.34 mmol) and2,2-dimethyl-1,3-dioxolane-4-methanamine (0.14 mL, 1.0 mmol) by themethod of Example 6. Title compound obtained as a pale-yellow solid (94mg, 57%). δ_(H) (DMSO-d₆) 10.68 (1H, s), 8.36-8.35 (1H, m), 8.20 (1H,dd, J 1.2, 8.2 Hz), 7.90-7.87 (1H, m), 7.76 (1H, dd, J 1.7, 10.4 Hz),7.62-7.59 (1H, m), 7.45-7.40 (2H, m), 4.86 (1H, d, J 5.0 Hz), 4.64 (1H,t, J 5.7 Hz), 3.72-3.64 (1H, m), 3.51-3.41 (3H, m), 3.40-3.34 (1H, m).LCMS (ES⁺) RT 2.91 minutes, 488 (M+H)⁺.

Example 8 Ethyl2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylate7-oxide

Prepared from Intermediate 1 (2.38 g, 8.58 mmol) and ethyl(2-chloro-1-oxidopyridin-3-yl)acetate (D. H. Bremner et al., Synthesis,1997, 949) (1.85 g, 8.58 mmol) by the method of Example 1. Titlecompound obtained as a pale yellow solid (3.10 g, 79%). δ_(H) (DMSO-d₆)10.31 (1H, br s), 8.20 (1H, d, J 5.9 Hz), 7.94 (1H, d, J 7.8 Hz), 7.89(1H, dd, J 1.8, 10.0 Hz), 7.72 (1H, d, J 8.4 Hz), 7.55-7.46 (2H, m),4.41 (2H, q, J 8.4 Hz), 1.40 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT 3.44minutes, 459 (M+H)⁺.

Example 9N-(2,3-Dihydroxypropyl)-2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxamide7-oxide

Prepared from Example 8 (200 mg, 0.43 mmol) and2,2-dimethyl-1,3-dioxolane-4-methanamine (0.18 mL, 1.3 mmol) by themethod of Example 6. Title compound obtained as a white solid (32 mg,15%). δ_(H) (DMSO-d₆) 10.60 (1H, s), 8.22 (1H, m), 7.90 (1H, s),7.84-7.76 (2H, m), 7.64-7.60 (1H, m), 7.45-7.40 (2H, m), 4.78 (1H, d, J4.9 Hz), 4.64 (1H, t, J 5.6 Hz), 3.70-3.60 (1H, m), 3.50-3.15 (4H, m).LCMS (ES⁻) RT 2.37 minutes, 502 (M−H)⁻.

Example 102-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonitrile

To a solution of (2-chloropyridin-3-yl)acetonitrile (D. H. Bremner etal., Synthesis, 1997, 949) (700 mg, 4.59 mmol) and Intermediate 1 (1.28g, 4.60 mmol) in dry DMSO (15 mL) was added sodium hydride (202 mg, 60%in mineral oil, 5.06 mmol). The mixture was stirred at room temperaturefor 15 minutes before heating to 90° C. for four hours. The reactionmixture was poured into water (80 mL) and the solid precipitate filteredand washed with water/ethanol (2:1 mixture, 50 mL) followed by diethylether/hexane (1:1 mixture, 20 mL). The solid was dried in a vacuum ovenand recrystallised from ethanol/water to give the title compound as apale brown solid (800 mg, 45%). δ_(H) (DMSO-d₆) 10.40 (1H, s), 8.37 (1H,dd, J 1.3, 4.6 Hz), 7.83-7.81 (2H, m), 7.64 (1H, d, J 8.3 Hz), 7.44 (1H,dd, J 4.7, 8.0 Hz), 7.33 (1H, dd, J 8.3, 8.3 Hz). LCMS RT 3.08 minutes,(ES⁻) 394 (M−H)⁻, (ES⁺) 396 (M+H)⁺.

Example 112-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic AcidAmide

A solution of Example 1 (250 mg, 0.56 mmol) in ethanol (5 mL) was addedto liquid ammonia (15 mL) and the mixture heated in a Parr apparatus to95° C. at 800 psi for 18 hours. The volatiles were removed in vacuo togive an oily brown residue. Repeated trituration with ethanol and DCMafforded the title compound as a white solid (18 mg). δ_(H) (DMSO-d₆)11.20 (1H, bs), 8.34 (1H, d, J 3.4 Hz), 8.20 (1H, dd, J 8.2, 1.3 Hz),7.76 (1H, dd, J 10.4, 1.8 Hz), 7.62 (1H, d, J 8.2 Hz), 7.57 (2H, br s),7.49-7.39 (2H, m). LCMS (ES⁺) RT 3.11 minutes, 412 (M+H)⁺.

Example 12[2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl](pyrrolidin-1-yl)methanone

Prepared from Example 1 (250 mg, 0.60 mmol) and pyrrolidine (0.25 mL, 3mmol) by the method of Example 2. Title compound obtained as a paleyellow solid (136 mg, 51%). δ_(H) (DMSO-d₆) 9.21 (1H, br s), 8.35 (1H,dd, J 1.6, 4.7 Hz), 7.81 (1H, dd, J 1.6, 8.1 Hz), 7.67 (1H, dd, J 1.9,10.5 Hz), 7.50-7.46 (1H, m), 7.35 (1H, dd, J 4.7, 8.1 Hz), 7.13 (1H, dd,J 8.6, 8.6 Hz), 3.32-3.30 (4H, m), 1.78-1.73 (4H, m). LCMS (ES⁺) RT 3.32minutes, 468 (M+H)⁺.

Example 132-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic Acid(3-hydroxypropyl)amide

Example 1 (500 mg, 1.13 mmol) was dissolved in dry toluene (6 mL) undernitrogen. To this solution was added trimethylaluminium (2.83 mL of a 2Msolution in hexane, 5.66 mmol) over 5 minutes. After 10 minutes asolution of Intermediate 3 (1.07 g, 5.66 mmol) in dry toluene (5 mL) wasadded and the reaction heated to 100° C. for 6 hours. The reaction wasallowed to cool to room temperature and treated with 2M HCl (10 mL) andwater (30 mL). The mixture was extracted with ethyl acetate (3×50 mL),then the organic phases were dried over Na₂SO₄ and filtered and thesolvents removed in vacuo. The crude residue was dissolved in methanol(30 mL), treated with 2M HCl (20 mL) and stirred at ambient temperaturefor 18 hours. The mixture was concentrated in vacuo, treated with 2MNaOH (20 mL) and extracted with ethyl acetate (3×50 mL). The organicphases were dried over Na₂SO₄, filtered, and the volatiles removed invacuo. The residual solid was triturated with diethyl ether (10 mL) anddried in a vacuum oven to give the title compound as a pale yellow solid(100 mg, 19%). δ_(H) (DMSO-d₆) 10.75 (1H, br s), 8.35 (1H, m), 8.17 (1H,d, J 7.9 Hz), 8.01 (1H, br s), 7.75 (1H, d, J 10.1 Hz), 7.59 (1H, d, J8.1 Hz), 7.44-7.41 (2H, m), 4.55 (1H, t, J 5.1 Hz), 3.54-3.48 (2H, m),3.41-3.34 (2H, m), 1.75-1.67 (2H, m). LCMS (ES⁺) RT 3.22 minutes, 472(M+H)⁺.

Example 142-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic Acid(2(S),3-dihydroxypropyl)amide

Prepared from Example 1 (1.0 g, 2.26 mmol) and(S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methylamine (1.48 g, 11.3 mmol) bythe method of Example 6. Title compound obtained as a white solid (425mg, 39%). δ_(H) (DMSO-d₆) 10.67 (1H, bs), 8.36 (1H, d, J 3.8 Hz), 8.20(1H, d, J 8.5 Hz), 7.88 (1H, bs), 7.76 (1H, d, J 10.5 Hz), 7.61 (1H, d,J 8.5 Hz), 7.46-7.40 (2H, m), 4.86 (1H, d, J 5.0 Hz), 4.64 (1H, t, J 5.7Hz), 3.72-3.67 (1H, m), 3.52-3.38 (3H, m), 3.30-3.22 (1H, m). LCMS (ES⁺)RT 2.91 minutes, 488 (M+H)⁺.

Example 152-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic Acid(2(R),3-dihydroxypropyl)amide

Prepared from Example 1 (500 mg, 1.13 mmol) and(R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methylamine (655 g, 4.52 mmol) bythe method of Example 6. Title compound obtained as a white solid (100mg, 18%). δ_(H) (DMSO-d₆) 10.67 (1H, bs), 8.36 (1H, d, J 3.8 Hz), 8.20(1H, d, J 8.5 Hz), 7.88 (1H, bs), 7.76 (1H, d, J 10.5 Hz), 7.61 (1H, d,J 8.5 Hz), 7.46-7.40 (2H, m), 4.86 (1H, d, J 5.0 Hz), 4.64 (1H, t, J 5.7Hz), 3.72-3.67 (1H, m), 3.52-3.38 (3H, m), 3.30-3.22 (1H, m). LCMS (ES⁺)RT 2.91 minutes, 488 (M+H)⁺.

Example 162-[(4-Bromo-2-fluorophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic AcidMethylamide

Prepared from Intermediate 2 (150 mg, 0.38 mmol) and a 2M solution ofmethylamine in THF (0.95 mL, 1.9 mmol) by the method of Example 2. Titlecompound obtained as a white solid (125 mg, 87%). δ_(H) (DMSO-d₆) 10.83(1H, bs), 8.35 (1H, dd, J 1.4, 4.6 Hz), 8.18 (1H, dd, J 1.4, 8.2 Hz),7.92 (1H, bs), 7.69 (1H, dd, J 2.1, 10.6 Hz), 7.59 (1H, dd, J 8.8, 8.8Hz), 7.48-7.43 (1H, m), 7.42 (1H, dd, J 8.2, 4.6 Hz), 2.83 (3H, d, J 4.5Hz). LCMS (ES⁺) RT 3.45 minutes, 380/382 [Br⁷⁹/Br⁸¹] (M+H)⁺.

Example 17 2-[(4-Iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylicAcid Ethyl Ester

Prepared from ethyl (2-chloropyridin-3-yl)acetate (D. H. Bremner et al.,Synthesis, 1997, 949) (750 mg, 3.8 mmol) and 4-iodophenyl isothiocyanate(1.0 g, 3.8 mmol) by the method of Example 1. Title compound obtained asan off-white solid (800 mg, 50%). δ_(H) (DMSO-d₆) 10.34 (1H, br s),8.33-8.30 (2H, m), 7.79 (2H, dt, J 2.0, 6.7 Hz), 7.43-7.31 (3H, m), 4.40(2H, q, J 7.1 Hz), 1.40 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT 4.31 minutes,425 (M+H)⁺.

Example 182-[(4-Iodo-2-methylphenyl)amino]thieno[2,3-b]pyridine-3-carbonitrile

To a stirred solution of Intermediate 8 (429 mg, 3.28 mmol) and(2-chloropyridin-3-yl)acetonitrile (D. H. Bremner et al., Synthesis,1997, 949) (500 mg, 3.28 mmol) in DMSO (20 mL) was added sodium hydride(164 mg, 4.1 mmol). When evolution of gases had finished the reactionmixture was heated for 3 hours at 80° C. After this time the reactionmixture was poured onto ice and extracted into DCM (2×50 mL). Theorganics were dried (Na₂SO₄) and then evaporated in vacuo to give abrown residue. Column chromatography (SiO₂, 5:1 hexane:EtOAc) gave thetitle compound as a yellow powder (198 mg, 15%). δ_(H) (DMSO-d₆) 10.11(1H, s), 8.29 (1H, dd, J 1.5, 4.7 Hz), 7.75 (2H, m), 7.63 (1H, dd, J1.7, 8.1 Hz), 7.39 (1H, dd, J 8.1, 4.8 Hz), 7.19 (1H, d, J 8.3 Hz), 2.24(3H, s). LCMS (ES⁺) RT 3.68 minutes, 392 (M+H)⁺.

Example 192-[(4-Bromo-2-fluorophenyl)amino]thieno[2,3-b]pyridine-3-carbonitrile

4-Bromo-2-fluoro-1-isothiocyanatobenzene (250 mg, 1.08 mmol) and(2-chloropyridin-3-yl)acetonitrile (D. H. Bremner et al., Synthesis,1997, 949) (165 mg, 1.08 mmol) were stirred in DMSO (20 mL) and sodiumhydride (52 mg, 1.3 mmol) added portionwise. After evolution of gaseshad finished the reaction mixture was heated for 4 h at 80° C. Afterthis time the reaction mixture was added to ice (50 mL) and aprecipitate formed. This was filtered and purified by preparative HPLC(pH 10, 2-3 min) to give the title compound as a white powder (30 mg,9%). δ_(H) (DMSO-d₆) 10.45 (1H, s), 8.31 (1H, d, J 3.9 Hz), 7.75 (2H,m), 7.51-7.38 (3H, m). LCMS (ES⁺) RT 3.49 minutes, 350 (M+H)⁺.

Example 202-[(2-Chloro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonitrile

Intermediate 9 (300 mg, 1.01 mmol) and(2-chloropyridin-3-yl)acetonitrile (D. H. Bremner et al., Synthesis,1997, 949) (165 mg, 1.01 mmol) were stirred together in DMSO (20 mL) andsodium hydride (48 mg, 1.21 mmol) was added portionwise. After evolutionof gases was complete the reaction mixture was heated for 4 h at 80° C.After this time the reaction mixture was added to ice (50 mL) and thenextracted into DCM (2×50 mL), which was dried (Na₂SO₄) and evaporated invacuo to give a yellow residue. This residue was subjected to columnchromatography (SiO₂, 1:4 EtOAc:hexane) to afford the title compound asa yellow powder (118 mg, 28%). δ_(H) (DMSO-d₆) 10.38 (1H, s), 8.35 (1H,dd, J 1.5, 4.8 Hz), 8.00 (1H, d, J 1.9 Hz), 7.80 (2H, m), 7.42 (1H, dd,J 8.0, 4.8 Hz), 7.35 (1H, d, J 8.3 Hz). LCMS (ES⁺) RT 3.70 minutes, 412(M+H)⁺.

Example 212-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic Acid(2-amino-2-methylpropyl)amide

Trimethylaluminium (2.85 mL of a 2M solution in hexane, 5.7 mmol) wasadded to a solution of 1,2-diamino-2-methylpropane (498 mg, 5.7 mmol) intoluene (5 mL). After 10 minutes Example 1 (500 mg, 1.13 mmol) was addedand the mixture heated at 100° C. for 4 h. After cooling the reactionwas quenched with 10% sodium hydroxide solution (75 mL) and extractedwith EtOAc (100 mL). The organic phase was dried (Na₂SO₄) andconcentrated in vacuo to give a solid. Trituration with hexanes (30 mL)and filtration gave the title compound as a yellow solid (248 mg, 45%).δ_(H) (DMSO-d₆) 10.72 (1H, m), 8.43 (1H, dd, J 1.7, 8.0 Hz), 7.84 (1H,dd, J 1.7, 4.7 Hz), 7.80-7.40 (2H, s), 7.46-7.35 (2H, m), 7.21 (1H, m),7.00 (1H, dd, J 4.7, 8.0 Hz), 3.40 (2H, d, J 5.7 Hz), 1.25 (6H, s). LCMS(ES⁺) RT 2.23 minutes, 501 (M+H)⁺.

Example 222-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid[(4R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]amide

1-(3-Dimethylaminopropyl)-3-carbodiimide hydrochloride (131 mg, 0.68mmol) was added to a solution of Intermediate 7 (142 mg, 0.34 mmol),1-hydroxybenzotriazole (93 mg, 0.68 mmol), N-methylmorpholine (0.10 mL,0.94 mmol) and (4R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxylamine (WO02/006213) (101 mg, 0.68 mmol) in N,N-dimethylformamide (5 mL). Thereaction mixture was stirred at r.t. for 20 h, then poured into EtOAc(25 mL). The organic solution was washed with sat. brine (2×25 mL), thendried (Na₂SO₄), filtered and concentrated in vacuo to give a brownsolid. The crude product was subjected to column chromatography (SiO₂,2:1 hexanes/EtOAc) to give the title compound as a pale yellow powder(135 mg, 95%). δ_(H) (DMSO-d₆) 10.98 (1H, s), 8.74 (1H, s), 8.28-8.26(1H, m), 7.94-7.91 (1H, m), 7.48-7.46 (2H, m), 7.37-7.32 (1H, m), 7.23(1H, dd, J 4.8, 8.2 Hz), 4.46-4.40 (1H, m), 4.17 (1H, dd, J 3.8, 11.7Hz), 4.11-4.01 (2H, m), 3.79 (1H, dd, J 7.0, 8.3 Hz), 1.15 (3H, s), 1.10(3H, s). LCMS RT 3.38 minutes, (ES⁻) 542 (M−H)⁻, (ES⁺) 544 (M+H)⁺.

Example 232-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid[(2R)-2,3-dihydroxypropoxy]amide

A solution of Example 22 (125 mg, 0.23 mmol) in methanol (5 mL) and THF(5 mL) was treated with 10% aq. HCl (5 mL). The reaction mixture wasstirred for 3.5 h at r.t., then diluted with EtOAc (25 mL). The organicsolution was washed with sat. brine (2×25 mL), then dried (Na₂SO₄),filtered and concentrated in vacuo to give the title compound as a whitepowder, which was washed with EtOAc, then hexanes, and dried undersuction (76 mg, 66%). δ_(H) (DMSO-d₆) 11.31 (1H, s), 10.33 (1H, s),8.34-8.33 (1H, m), 8.12-8.09 (1H, m), 7.79-7.76 (1H, m), 7.63-7.60 (1H,m), 7.45-7.40 (2H, m), 4.89-4.88 (1H, m), 4.62-4.59 (1H, m), 3.99-3.97(1H, m), 3.85-3.80 (2H, m), 3.43 (2H, m). LCMS RT 3.38 minutes, (ES⁻)502 (M−H)⁻, (ES⁺) 504 (M+H)⁺.

Example 24(1-{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}piperidin-4-yl)-carbamicAcid Tert-Butyl Ester

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and 4-(BOC-amino)-piperidine (145 mg, 0.72 mmol), by the method ofExample 22. The title compound was evaporated from ether to give acolourless hard foam (111 mg, 51%). δ_(H) (CDCl₃, contains rotamers)9.17 (0.64H, s), 8.90 (0.36H, s), 8.39-8.37 (1H, m), 7.75-7.73 (0.36H,m), 7.66-7.63 (0.64H, m), 7.53-7.50 (2H, m), 7.44-7.39 (1H, m),7.31-7.28 (1H, m), 4.57 (0.36H, m), 4.40 (0.64H, m), 4.20-4.15 (1.28H,m), 4.03-3.98 (0.72H, m), 3.72 (1H, m), 3.16-3.08 (2H, m), 2.05-2.00(2H, m), 1.47 (3.2H, s), 1.44 (5.8H, s), 1.36-1.28 (2H, m). LCMS RT 3.36minutes, (ES⁻) 595 (M−H)⁻, (ES⁺) 597 (M+H)⁺.

Example 252-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic Acid(4-aminopiperidin-1-yl)amide Dihydrochloride

A solution of Example 24 (99 mg, 0.17 mmol) in methanol (2 mL) wastreated with 4M HCl in 1,4-dioxane (5 mL) and stirred at r.t. for 3 h.The reaction mixture was concentrated in vacuo to give a yellow gum,which was dissolved in water (25 mL). The aqueous solution was washedwith ether (2×25 mL), and then evaporated in vacuo. The resulting gumwas triturated with ether to give the title compound as a yellow powder(89 mg, 94%). δ_(H) (DMSO-d₆, contains rotamers) 9.24 (0.5H, s), 9.14(0.5H, s), 8.38-8.37 (1H, m), 8.13 (3H, br s), 7.82-7.75 (1H, m),7.72-7.66 (1H, m), 7.55-7.47 (1H, m), 7.38 (1H, dd, J 4.7, 8.1 Hz),7.23-7.10 (1H, m), 4.02 (2H, br m), 3.25 (1H, br m), 3.06-2.98 (1H, m),2.88-2.81 (1H, m), 1.93-1.89 (2H, m), 1.43 (2H, br m). LCMS RT 2.86minutes, (ES⁺) 497 (M+H)⁺.

Example 262-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic Acid(2-hydroxy-1-methylethyl)amide

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and 2-aminopropanol (0.06 mL, 0.72 mmol), by the method of Example22. The crude product was subjected to column chromatography (SiO₂, 1:1hexanes/EtOAc) to give the title compound, which was recrystallised fromEtOAc/hexanes to give a beige powder (56 mg, 33%). δ_(H) (DMSO-d₆) 10.45(1H, s), 8.37-8.36 (1H, m), 8.16-8.13 (1H, m), 7.76-7.71 (2H, m),7.60-7.57 (1H, m), 7.46-7.36 (2H, m), 4.78 (1H, t, J 5.6 Hz), 4.10-4.03(1H, m), 3.52-3.35 (2H, m), 1.13 (3H, d, J 6.7 Hz). LCMS RT 3.46minutes, (ES⁺) 472 (M+H)⁺.

Example 273-[({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}amino)methyl]-azetidine-1-carboxylicAcid Tert-Butyl Ester

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and 1-BOC-3-(aminomethyl)azetidine (135 mg, 0.72 mmol), by themethod of Example 22. The crude product was subjected to columnchromatography (SiO₂, 3:2 hexanes/EtOAc) to give the title compound,which was recrystallised from ether/hexanes to give a cream-colouredpowder (116 mg, 55%). δ_(H) (CDCl₃) 8.37 (1H, dd, J 1.3, 4.7 Hz), 7.84(1H, dd, J 1.3, 8.2 Hz), 7.56-7.53 (2H, m), 7.46-7.41 (1H, m), 7.32 (1H,dd, J 4.7, 8.2 Hz), 6.08 (1H, m), 4.14-4.09 (2H, m), 3.77-3.73 (4H, m),2.94-2.92 (1H, m), 1.46 (9H, s). LCMS RT 3.68 minutes, (ES⁻) 581 (M−H)⁻,(ES⁺) 583 (M+H)⁺.

Example 28(1-{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}azetidin-3-ylmethyl)carbamicAcid Tert-Butyl Ester

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and 3-(BOC-aminomethyl)-azetidine (135 mg, 0.72 mmol), by themethod of Example 22. The title compound was evaporated from ether togive a colourless hard foam (75 mg, 36%). δ_(H) (CDCl₃) 8.25 (1H, dd, J1.5, 4.7 Hz), 7.67 (1H, dd, J 1.5, 8.1 Hz), 7.46-7.41 (2H, m), 7.38-7.33(1H, m), 7.22 (1H, dd, J 4.7, 8.1 Hz), 4.59 (1H, br s), 4.15-4.09 (2H,m), 3.80-3.75 (2H, m), 3.32 (2H, m), 2.78-2.74 (1H, m), 1.35 (9H, s).LCMS RT 3.41 minutes, (ES⁻) 581 (M−H)⁻, (ES⁺) 583 (M+H)⁺.

Example 293-({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}amino)azetidine-1-carboxylicAcid Tert-Butyl Ester

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and 1-BOC-3-aminoazetidine (125 mg, 0.72 mmol), by the method ofExample 22. The title compound was recrystallised from ether/hexanes togive a cream-coloured powder (116 mg, 57%). δ_(H) (CDCl₃) 8.38 (1H, dd,J 1.2, 4.7 Hz), 7.90 (1H, dd, J 1.2, 8.1 Hz), 7.56-7.53 (2H, m),7.45-7.40 (1H, m), 7.35 (1H, dd, J 4.7, 8.1 Hz), 6.19 (1H, d, J 6.9 Hz),4.89-4.84 (1H, m), 4.44-4.38 (2H, m), 3.93-3.88 (2H, m), 1.48 (9H, s).LCMS RT 3.66 minutes, (ES⁻) 567 (M−H)⁻, (ES⁺) 569 (M+H)⁺.

Example 30[3-(Aminomethyl)azetidin-1-yl]-{2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-methanone

A solution of Example 28 (65 mg, 0.11 mmol) in DCM (7 mL) was treatedwith trifluoroacetic acid (3 mL) and stirred for 1 h at r.t. Thereaction mixture was concentrated in vacuo to give a yellow gum, whichwas dissolved in water (25 mL) and basified to pH 10 with sodiumcarbonate. The aqueous solution was extracted with 5% methanol in DCM(4×25 mL), and the extracts combined, then dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was subjected to columnchromatography (SiO₂, 4:1 DCM/methanol) to give the title compound as agummy solid, which was triturated from ether to give a cream-colouredpowder (34 mg, 63%). δ_(H) (DMSO-d₆) 8.31 (1H, m), 7.93 (1H, m), 7.72(1H, dd, J 1.5, 10.5 Hz), 7.55 (1H, m), 7.37 (1H, dd, J 4.6, 8.1 Hz),7.29-7.24 (1H, m), 4.88 (2H, br s), 4.03-3.97 (2H, m), 3.71-3.67 (2H,m), 2.65 (1H, m), 2.70-2.68 (2H, m). LCMS RT 2.93 minutes, (ES⁻) 481(M−H)⁻, (ES⁺) 483 (M+H)⁺.

Example 312-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic Acid[(2R)-pyrrolidin-2-ylmethyl]amide

A solution of Intermediate 10 (135 mg, 0.23 mmol) in methanol (2 ml) wastreated with 4M HCl in 1,4-dioxane (5 mL) and stirred at r.t. for 30min. The reaction mixture was concentrated in vacuo to give a yellowgum, which was dissolved in water (25 mL). The aqueous solution waswashed with ether (2×25 mL), then basified to pH 11 with 25% aq.ammonium hydroxide. The aqueous solution was extracted with DCM (2×25mL), and the organic extracts combined, dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was subjected to columnchromatography (SiO₂, 91:8:1 DCM/methanol/25% aq. ammonium hydroxide) togive the title compound, which was freeze-dried overnight fromacetonitrile/water to give a cream-coloured powder (73 mg, 65%). δ_(H)(DMSO-d₆) 10.63 (1H, s), 9.12 (1H, br s), 8.37 (1H, dd, J 1.7, 8.0 Hz),7.84 (1H, dd, J 1.7, 4.7 Hz), 7.47 (1H, dd, J 2.0, 10.4 Hz), 7.42-7.38(1H, m), 7.17-7.11 (1H, m), 7.00 (1H, dd, J 4.7, 8.0 Hz), 3.68-3.61 (1H,m), 3.51-3.49 (2H, m), 3.17-3.12 (2H, m), 2.28-1.62 (4H, m). LCMS RT2.42 minutes, (ES⁻) 495 (M−H)⁻, (ES⁺) 497 (M+H)⁺.

Example 322-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic Acid[(2S)-pyrrolidin-2-ylmethyl]amide

Prepared from Intermediate 11 (139 mg, 0.23 mmol) by the method ofExample 31. The title compound was obtained as a cream-coloured powder(81 mg, 70%). OH (DMSO-d₆) 10.63 (1H, s), 9.12 (1H, br s), 8.37 (1H, dd,J 1.7, 8.0 Hz), 7.84 (1H, dd, J 1.7, 4.7 Hz), 7.47 (1H, dd, J 2.0, 10.4Hz), 7.42-7.38 (1H, m), 7.17-7.11 (1H, m), 7.00 (1H, dd, J 4.7, 8.0 Hz),3.68-3.61 (1H, m), 3.51-3.49 (2H, m), 3.17-3.12 (2H, m), 2.28-1.62 (4H,m). LCMS RT 2.42 minutes, (ES⁻) 495 (M−H)⁻, (ES⁺) 497 (M+H)⁺.

Example 33(3S)-3-({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}amino)-piperidine-1-carboxylicAcid Tert-Butyl Ester

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and (S)-1-BOC-3-aminopiperidine (145 mg, 0.72 mmol), by the methodof Example 22. The title compound was obtained as a gummy yellow solid(131 mg, 61%). δ_(H) (CDCl₃) 11.34 (1H, s), 8.36-8.34 (1H, m), 7.90-7.88(1H, m), 7.55-7.52 (2H, m), 7.45-7.42 (1H, m), 7.32-7.29 (1H, m), 5.32(1H, br s), 4.31 (1H, m), 3.83-3.78 (2H, m), 3.46-3.42 (1H, m), 3.17(1H, m), 1.89-1.73 (2H, m), 1.67 (2H, m), 1.47 (9H, s). LCMS RT 4.04minutes, (ES⁺) 597 (M+H)⁺.

Example 34(3R)-3-({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}amino)-piperidine-1-carboxylicAcid Tert-Butyl Ester

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and (R)-1-BOC-3-aminopiperidine (145 mg, 0.72 mmol), by the methodof Example 22. The title compound was obtained as a pale pink gummysolid (136 mg, 63%). δ_(H) (CDCl₃) 11.34 (1H, s), 8.36-8.34 (1H, m),7.90-7.88 (1H, m), 7.55-7.52 (2H, m), 7.45-7.42 (1H, m), 7.32-7.29 (1H,m), 5.32 (1H, br s), 4.31 (1H, m), 3.83-3.78 (2H, m), 3.46-3.42 (1H, m),3.17 (1H, m), 1.89-1.73 (2H, m), 1.67 (2H, m), 1.47 (9H, s). LCMS RT4.03 minutes, (ES⁺) 597 (M+H)⁺.

Example 352-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic Acid[(3S)-piperidin-3-yl]amide Dihydrochloride

A solution of Example 33 (120 mg, 0.20 mmol) in methanol (2 mL) wastreated with 4M HCl in 1,4-dioxane (5 mL) and stirred at r.t. for 3 h.The reaction mixture was evaporated in vacuo to give the title compoundas a gummy yellow solid, which was triturated from ether to give ayellow powder (112 mg, 98%). δ_(H) (DMSO-d₆) 10.38 (1H, s), 9.04-8.92(2H, m), 8.38 (1H, dd, J 1.3, 4.6 Hz), 8.17-8.14 (2H, m), 7.75 (1H, dd,J 1.8, 10.4 Hz), 7.61-7.58 (1H, m), 7.44 (1H, dd, J 4.6, 8.2 Hz),7.42-7.36 (1H, m), 4.09 (1H, m), 3.34-3.31 (1H, m), 3.21-3.17 (1H, m),2.94-2.79 (2H, m), 1.91 (2H, m), 1.74-1.61 (2H, m). LCMS RT 2.38minutes, (ES⁺) 497 (M+H)⁺.

Example 362-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic Acid[(3R)-piperidin-3-yl]amide Dihydrochloride

Prepared from Example 34 (126 mg, 0.21 mmol) by the method of Example35.

The title compound was obtained as a yellow powder (115 mg, 96%). δ_(H)(DMSO-d₆) 10.38 (1H, s), 9.04-8.92 (2H, m), 8.38 (1H, dd, J 1.3, 4.6Hz), 8.17-8.14 (2H, m), 7.75 (1H, dd, J 1.8, 10.4 Hz), 7.61-7.58 (1H,m), 7.44 (1H, dd, J 4.6, 8.2 Hz), 7.42-7.36 (1H, m), 4.09 (1H, m),3.34-3.31 (1H, m), 3.21-3.17 (1H, m), 2.94-2.79 (2H, m), 1.91 (2H, m),1.74-1.61 (2H, m). LCMS RT 2.38 minutes, (ES⁺) 497 (M+H)⁺.

Example 37(1-{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}-(3R)-pyrrolidin-3-yl)carbamicAcid Tert-Butyl Ester

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and (R)-3-(BOC-amino)-pyrrolidine (186 mg, 0.72 mmol), by themethod of Example 22. The crude product was subjected to columnchromatography (SiO₂, 3:2 hexanes/EtOAc) to give the title compound,which was evaporated from ether to give a colourless hard foam (110 mg,52%). δ_(H) (CDCl₃) 9.03 (1H, s), 8.28 (1H, dd, J 1.5, 4.7 Hz), 7.56(1H, dd, J 1.5, 8.1 Hz), 7.43-7.39 (2H, m), 7.34-7.29 (1H, m), 7.22-7.18(1H, m), 4.50 (1H, br s), 4.16-4.14 (1H, m), 3.71 (1H, dd, J 6.2, 11.8Hz), 3.63-3.56 (2H, m), 3.30 (1H, dd, J 5.1, 11.8 Hz), 2.19-2.12 (1H,m), 1.86-1.77 (1H, m), 1.35 (9H, s). LCMS RT 3.33 minutes, (ES⁻) 581(M−H)⁻, (ES⁺) 583 (M+H)⁺.

Example 38(1-{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}-(3S)-pyrrolidin-3-yl)carbamicAcid Tert-Butyl Ester

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and (S)-3-(BOC-amino)-pyrrolidine (186 mg, 0.72 mmol), by themethod of Example 37. The title compound was obtained as a colourlesshard foam (125 mg, 59%). δ_(H) (CDCl₃) 9.03 (1H, s), 8.28 (1H, dd, J1.5, 4.7 Hz), 7.56 (1H, dd, J 1.5, 8.1 Hz), 7.43-7.39 (2H, m), 7.34-7.29(1H, m), 7.22-7.18 (1H, m), 4.50 (1H, br s), 4.16-4.14 (1H, m), 3.71(1H, dd, J 6.2, 11.8 Hz), 3.63-3.56 (2H, m), 3.30 (1H, dd, J 5.1, 11.8Hz), 2.19-2.12 (1H, m), 1.86-1.77 (1H, m), 1.35 (9H, s). LCMS RT 3.33minutes, (ES⁻) 581 (M−H)⁻, (ES⁺) 583 (M+H)⁺.

Example 39(1-{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}azetidin-3-yl)-carbamicAcid Tert-Butyl Ester

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and 3-(BOC-amino)azetidine (125 mg, 0.72 mmol), by the method ofExample 22. The crude product was subjected to column chromatography(SiO₂, 3:1 hexanes/EtOAc) to give the title compound, which wasevaporated from ether to a cream-coloured powder (100 mg, 49%). δ_(H)(CDCl₃) 10.11 (1H, s), 8.35 (1H, dd, J 1.5, 4.7 Hz), 7.76 (1H, dd, J1.5, 8.1 Hz), 7.55-7.51 (2H, m), 7.47-7.41 (1H, m), 7.31 (1H, dd, J 4.7.8.1 Hz), 4.95 (1H, br s), 4.52 (1H, br s), 4.46-4.40 (2H, m), 4.01-3.96(2H, m), 1.45 (9H, s). LCMS RT 3.47 minutes, (ES⁻) 567 (M−H)⁻, (ES⁺) 569(M+H)⁺.

Example 404-({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}amino)-piperidine-1-carboxylicAcid Tert-Butyl Ester

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and 4-amino-1-BOC-piperidine (145 mg, 0.72 mmol), by the method ofExample 22. The crude product was adsorbed onto SiO₂ and subjected tocolumn chromatography (SiO₂, 2:1 hexanes/EtOAc) to give the titlecompound, which was evaporated from ether to give cream-coloured flakes(97 mg, 45%). δ_(H) (CDCl₃) 11.18 (1H, s), 8.36 (1H, dd, J 1.4, 4.7 Hz),7.81 (1H, dd, J 1.4, 8.2 Hz), 7.55-7.53 (2H, m), 7.46-7.41 (1H, m), 7.32(1H, dd, J 4.7. 8.2 Hz), 5.74 (1H, d, J 7.6 Hz), 4.27-4.20 (1H, m),4.15-4.11 (2H, m), 3.03-2.96 (2H, m), 2.15-2.10 (2H, m), 1.50 (9H, s),1.45 (2H, m). LCMS RT 3.95 minutes, (ES⁻) 567 (M−H)⁻, (ES⁺) 569 (M+H)⁺.

Example 41[(3R)-3-Aminopyrrolidin-1-yl]-{2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-methanone

Prepared from Example 37 (100 mg, 0.17 mmol) following the method ofExample 35. The title compound was obtained as a yellow powder (100 mg,quant.). OH (DMSO-d₆) 9.29 (1H, s), 8.36 (1H, dd, J 1.5, 4.7 Hz), 8.29(3H, s), 7.91-7.89 (1H, m), 7.72 (1H, dd, J 1.8, 10.4 Hz), 7.55-7.52(1H, m), 7.37 (1H, dd, J 4.7, 8.1 Hz), 7.24-7.19 (1H, m), 3.79-3.72 (1H,m), 3.70-3.58 (2H, m), 3.51-3.38 (2H, m), 2.20-2.13 (1H, m), 2.01-1.97(1H, m). LCMS RT 2.24 minutes, (ES⁻) 481 (M−H)⁻, (ES⁺) 483 (M+H)⁺.

Example 42[(3S)-3-Aminopyrrolidin-1-yl]-{2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-methanone

Prepared from Example 38 (115 mg, 0.20 mmol) following the method ofExample 35. The title compound was obtained as a yellow powder (109 mg,99%). OH (DMSO-d₆) 9.29 (1H, s), 8.36 (1H, dd, J 1.5, 4.7 Hz), 8.29 (3H,s), 7.91-7.89 (1H, m), 7.72 (1H, dd, J 1.8, 10.4 Hz), 7.55-7.52 (1H, m),7.37 (1H, dd, J 4.7, 8.1 Hz), 7.24-7.19 (1H, m), 3.79-3.72 (1H, m),3.70-3.58 (2H, m), 3.51-3.38 (2H, m), 2.20-2.13 (1H, m), 2.01-1.97 (1H,m). LCMS RT 2.24 minutes, (ES⁻) 481 (M−H)⁻, (ES⁺) 483 (M+H)⁺.

Example 432-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic Acid(piperidin-4-yl)amide

Prepared from Example 40 (87 mg, 0.15 mmol) following the method ofExample 35. The title compound was obtained as a yellow powder (80 mg,96%). δ_(H) (DMSO-d₆) 10.31 (1H, s), 8.84 (1H, m), 8.68 (1H, m), 8.38(1H, dd, J 1.3, 4.6 Hz), 8.24 (1H, d, J 7.5 Hz), 8.09 (1H, dd, J 1.3,8.2 Hz), 7.74 (1H, dd, J 1.8, 10.5 Hz), 7.59-7.57 (1H, m), 7.44 (1H, dd,J 4.7, 8.2 Hz), 7.39-7.34 (1H, m), 4.05-3.97 (1H, m), 3.32-3.27 (2H, m),3.03-2.87 (2H, m), 2.00-1.97 (2H, m), 1.82-1.71 (2H, m). LCMS RT 2.40minutes, (ES⁻) 495 (M−H)⁻, (ES⁺) 497 (M+H)⁺.

Example 44(3-Aminoazetidin-1-yl)-{2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl]-methanone

Prepared from Example 39 (90 mg, 0.16 mmol) by the method of Example 30.The reaction mixture was concentrated in vacuo to give a yellow gum,which was dissolved in methanol (5 mL) and water (5 mL) and basified topH 10 with 25% aq. ammonium hydroxide. The aqueous solution wasconcentrated in vacuo onto SiO₂, and the crude product was subjected tocolumn chromatography (SiO₂, 95:4:1 DCM/methanol/25% aq. ammoniumhydroxide). The title compound was freeze-dried overnight fromacetonitrile/methanol/water to give a cream-coloured powder (31 mg,42%). δ_(H) (DMSO-d₆) 8.33 (1H, dd, J 1.5, 4.7 Hz), 7.94 (1H, dd, J 1.5,8.1 Hz), 7.73 (1H, dd, J 1.9, 10.5 Hz), 7.54 (1H, ddd, J 0.9, 0.9, 8.4Hz), 7.38 (1H, dd, J 4.7, 8.1 Hz), 7.31-7.26 (1H, m), 4.23-4.11 (2H, m),3.72-3.59 (3H, m). LCMS RT 3.00 minutes, (ES⁻) 467 (M−H)⁻, (ES⁺) 469(M+H)⁺.

Example 452-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic Acidbis(2-hydroxyethyl)amide

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and diethanolamine (76 mg, 0.72 mmol), by the method of Example22. The crude product was subjected to column chromatography (SiO₂,EtOAc, twice) to give the title compound, which was freeze-driedovernight from acetonitrile/water to give a cream-coloured powder (62mg, 34%). δ_(H) (DMSO-d₆) 8.79 (1H, br s), 8.38 (1H, dd, J 1.5, 4.7 Hz),7.77 (1H, dd, J 1.5, 8.1 Hz), 7.67 (1H, dd, J 1.9, 10.5 Hz), 7.69-7.46(1H, m), 7.38 (1H, dd, J 4.7, 8.1 Hz), 7.18-7.12 (1H, m), 4.83 (2H, brs), 3.30 (8H, s). LCMS RT 3.01 minutes, (ES⁺) 502 (M+H)⁺.

Example 46{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}1-(3-hydroxyazetidin-1-yl)-methanone

Prepared from Intermediate 7 (225 mg, 0.54 mmol), 1-hydroxybenzotriazole(147 mg, 1.08 mmol), N-methylmorpholine (0.16 mL, 1.48 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (208 mg, 1.08mmol) and 3-hydroxyazetidine hydrochloride (120 mg, 1.08 mmol), by themethod of Example 22. After chromatography, the title compound wasrecrystallised from methanol/ether to give a white powder (125 mg, 49%).δ_(H) (DMSO-d₆) 9.60 (1H, s), 8.35-8.34 (1H, m), 7.94 (1H, dd, J 1.4,8.1 Hz), 7.75-7.71 (1H, m), 7.57-7.54 (1H, m), 7.41-7.37 (1H, m),7.31-7.25 (1H, m), 5.68 (1H, d, J 6.0 Hz), 4.47-4.44 (1H, m), 4.21-4.16(2H, m), 3.79-3.74 (2H, m). LCMS RT 3.31 minutes, (ES⁺) 470 (M+H)⁺.

Example 47{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-[(3R)-3-hydroxypyrrolidin-1-yl]-methanone

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and (R)-3-hydroxypyrrolidine (63 mg, 0.72 mmol), by the method ofExample 22. After chromatography, the title compound was freeze-driedovernight from acetonitrile/water to give a cream-coloured powder (116mg, 66%). δ_(H) (DMSO-d₆) 9.20 (1H, s), 8.35 (1H, dd, J 1.5, 4.7 Hz),7.81 (1H, dd, J 1.5, 8.1 Hz), 7.67 (1H, dd, J 1.9, 10.5 Hz), 7.50-7.47(1H, m), 7.36 (1H, dd, J 4.7, 8.1 Hz), 7.17-7.11 (1H, m), 4.91 (1H, s),4.22 (1H, s), 3.54-3.30 (3H, m), 3.21-3.17 (1H, m), 1.90-1.74 (2H, m).LCMS RT 3.18 minutes, (ES⁺) 484 (M+H)⁺.

Example 48{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-[(3S)-3-hydroxypyrrolidin-1-yl]-methanone

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and (S)-3-hydroxypyrrolidine (63 mg, 0.72 mmol), by the method ofExample 47. The title compound was obtained as a cream-coloured powder(105 mg, 60%). δ_(H) (DMSO-d₆) 9.20 (1H, s), 8.35 (1H, dd, J 1.5, 4.7Hz), 7.81 (1H, dd, J 1.5, 8.1 Hz), 7.67 (1H, dd, J 1.9, 10.5 Hz),7.50-7.47 (1H, m), 7.36 (1H, dd, J 4.7, 8.1 Hz), 7.17-7.11 (1H, m), 4.91(1H, s), 4.22 (1H, s), 3.54-3.30 (3H, m), 3.21-3.17 (1H, m), 1.90-1.74(2H, m). LCMS RT 3.17 minutes, (ES⁺) 484 (M+H)⁺.

Example 49{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-[2-(hydroxymethyl)-piperidin-1-yl]-methanone

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and 2-piperidinemethanol (83 mg, 0.72 mmol), by the method ofExample 22. After chromatography, the title compound was recrystallisedfrom EtOAc/hexanes to give a pale yellow powder (44 mg, 24%). δ_(H)(DMSO-d₆, 130° C.) 8.38 (1H, dd, J 1.5, 4.7 Hz), 7.83 (1H, dd, J 1.5,8.0 Hz), 7.59 (1H, dd, J 1.9, 10.5 Hz), 7.47 (1H, d, J 8.5 Hz), 7.35(1H, dd, J 4.7, 8.0 Hz), 7.16 (1H, dd, J 8.8, 8.8 Hz), 4.30 (1H, br s),4.21 (1H, m), 3.89 (1H, m), 3.65-3.60 (1H, m), 3.51-3.47 (1H, m),3.03-2.97 (1H, m), 1.74-1.72 (1H, m), 1.65-1.56 (4H, m), 1.37 (1H, m).LCMS RT 2.86 minutes, (ES⁻) 510 (M−H)⁻, (ES⁺) 512 (M+H)⁺.

Example 50{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-[(3S)-3-(hydroxymethyl)-morpholin-4-yl]-methanone

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and (3S)-3-(hydroxymethyl)-morpholine (85 mg, 0.72 mmol), by themethod of Example 22. After chromatography, the title compound wasfreeze-dried overnight from acetonitrile/water to give a cream-colouredpowder (81 mg, 44%). δ_(H) (DMSO-d₆, 120° C.) 8.37-8.36 (1H, m),7.85-7.83 (1H, m), 7.60 (1H, dd, J 1.8, 10.5 Hz), 7.49-7.47 (1H, m),7.35 (1H, dd, J 4.7, 8.0 Hz), 7.15 (1H, dd, J 8.7, 8.7 Hz), 3.99 (1H,m), 3.85 (1H, d, J 11.6 Hz), 3.80-3.77 (1H, m), 3.70-3.67 (1H, m),3.65-3.56 (2H, m), 3.48-3.45 (1H, m), 3.34 (1H, m), 3.27-3.21 (1H, m).LCMS RT 2.60 minutes, (ES⁻) 512 (M−H)⁻, (ES⁺) 514 (M+H)⁺.

Example 514-{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}-(3R)-3-(hydroxymethyl)piperazine-1-carboxylicAcid Tert-Butyl Ester

Prepared from Intermediate 7 (150 mg, 0.36 mmol), 1-hydroxybenzotriazole(98 mg, 0.72 mmol), N-methylmorpholine (0.11 mL, 0.99 mmol),1-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride (139 mg, 0.72mmol) and (2R)-4-BOC-2-(hydroxymethyl)piperazine (157 mg, 0.72 mmol), bythe method of Example 22. The crude product was subjected to columnchromatography (SiO₂, 1:1 hexanes/EtOAc) to give the title compound,which was evaporated from ether to give a pale pink, hard foam (95 mg,43%). δ_(H) (DMSO-d₆, 120° C.) 8.53 (1H, br s), 8.38-8.37 (1H, m),7.86-7.84 (1H, m), 7.60 (1H, dd, J 1.7, 10.5 Hz), 7.49 (1H, d, J 8.5Hz), 7.36 (1H, dd, J 4.7, 8.0 Hz), 7.19-7.15 (1H, dd, J 8.5, 8.7 Hz),4.52 (1H, br s), 4.16 (1H, m), 3.95 (1H, d, J 13.5 Hz), 3.88-3.81 (2H,m), 3.49-3.43 (2H, m), 3.14-3.10 (1H, m), 3.02-2.95 (1H, m), 1.43 (9H,s). LCMS RT 2.98 minutes, (ES⁺) 613 (M+H)⁺.

Example 52 2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-7-oxide

Example 8 (250 mg, 0.55 mmol) was suspended in a mixture of ethanol (20mL) and water (10 mL). Lithium hydroxide hydrate (24.0 mg, 0.57 mmol)was added and the mixture heated to reflux for 24 hours. Afterconcentration and freeze-drying, the mixture was purified bychromatography (silica, dichloromethane then 2% MeOH indichloromethane). The title compound was obtained as an off-white solid(50 mg, 24%). δ_(H) (DMSO-d₆) 9.42 (1H, br s), 8.13 (1H, dd, J 0.7, 6.2Hz), 7.69 (1H, dd, J 1.9, 10.7 Hz), 7.54-7.51 (2H, m), 7.39-7.32 (2H,m), 6.73 (1H, s). LCMS (ES⁺) RT 2.84 minutes, 387 (M+H)⁺.

Example 532-[(2-Fluoro-4-iodophenyl)amino]-N-[2-(morpholin-4-yl)ethyl]thieno[2,3-b]pyridine-3-carboxamide

Prepared from Example 1 (250 mg, 0.56 mmol) and4-(2-aminoethyl)morpholine (292 mg, 2.24 mmol) by the method of Example5. After chromatography (5% methanol, 95% dichloromethane) the titlecompound was obtained as an off-white solid (140 mg, 47%). δ_(H) (CDCl₃)11.43 (1H, br s), 8.36 (1H, dd, J 1.4, 4.7 Hz), 8.03 (1H, dd, J 1.4, 8.2Hz), 7.55-7.51 (2H, m), 7.44 (1H, dd, J 8.2, 8.2 Hz), 7.32 (1H, dd, J4.7, 8.2 Hz), 6.84 (1H, br s), 3.80-3.77 (4H, m), 3.67-3.62 (2H, m),2.73-2.69 (2H, m), 2.62-2.59 (4H, m). LCMS (ES⁺) RT 2.37 minutes, 527(M+H)⁺.

Example 542-[4-({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}carbonyl)piperazin-1-yl]ethanol

Prepared from Example 1 (250 mg, 0.56 mmol) andN-(2-hydroxyethyl)piperazine (292 mg, 2.24 mmol) by the method ofExample 5. After chromatography (5% methanol, 95% dichloromethane) thetitle compound was obtained as a white solid (86 mg, 29%). δ_(H)(DMSO-d₆) 9.13 (1H, br s), 8.36 (1H, dd, J 1.5, 4.7 Hz), 7.80 (1H, dd, J1.5, 8.1 Hz), 7.68 (1H, dd, J 1.9, 10.5 Hz), 7.49-7.45 (1H, m), 7.37(1H, dd, J 4.7, 8.1 Hz), 7.10 (1H, dd, J 8.7, 8.7 Hz), 4.37 (1H, t, J5.4 Hz), 3.50-3.40 (6H, m), 2.37-2.33 (6H, m). LCMS (ES⁺) RT 2.16minutes, 527 (M+H)⁺.

Example 553-(1,4-Diazepan-1-ylcarbonyl)-N-(2-fluoro-4-iodophenyl)thieno[2,3-b]pyridin-2-amine

Prepared from Example 1 (250 mg, 0.56 mmol) and homopiperazine (224 mg,2.24 mmol) by the method of Example 5. After chromatography (10-15%methanol in dichloromethane) the title compound was obtained as a paleyellow solid (180 mg, 64%). δ_(H) (CDCl₃) 8.99 (1H, br s), 8.34 (1H, dd,J 1.6, 4.7 Hz), 7.74 (1H, dd, J 1.6, 8.1 Hz), 7.47-7.43 (2H, m), 7.35(1H, dd, J 8.5, 8.5 Hz), 7.28-7.22 (1H, m), 4.30-4.10 (1H, br m),3.95-3.80 (1H, br m), 3.39-2.86 (6H, br m), 2.17-1.77 (3H, br m). LCMS(ES⁺) RT 2.17 minutes, 497 (M+H)⁺.

Example 56N-[3-(Dimethylamino)-2,2-dimethylpropyl]-2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxamide

Prepared from Example 1 (250 mg, 0.56 mmol) andN,N,2,2-tetramethyl-1,3-propanediamine (292 mg, 2.24 mmol) by the methodof Example 5. After chromatography (5% methanol, 95% dichloromethane)the title compound was obtained as a pale yellow solid (60 mg, 20%).δ_(H) (DMSO-d₆) 10.81 (1H, br s), 9.10 (1H, br s), 8.24-8.21 (2H, m),7.69-7.65 (1H, m), 7.55-7.52 (1H, m), 7.37-7.31 (2H, m), 3.29-3.27 (2H,m), 2.50-2.37 (8H, br m), 0.96 (6H, s). LCMS (ES⁺) RT 2.39 minutes, 527(M+H)⁺.

Example 572-[(2-Fluoro-4-iodophenyl)amino]-N-[3-(morpholin-4-yl)propyl]thieno[2,3-b]pyridine-3-carboxamide

Prepared from Example 1 (250 mg, 0.56 mmol) and4-(3-aminopropyl)morpholine (323 mg, 2.24 mmol) by the method of Example5. After chromatography (5% methanol, 95% dichloromethane) the titlecompound was obtained as a pale yellow solid (115 mg, 38%). δ_(H)(CDCl₃) 11.29 (1H, br s), 8.36 (1H, dd, J 1.4, 4.7 Hz), 7.99 (1H, dd, J1.4, 8.2 Hz), 7.63-7.51 (2H, m), 7.47-7.41 (1H, m), 7.33-7.29 (1H, m),7.12 (1H, br s), 3.70-3.64 (2H, m), 3.60-3.56 (4H, m), 2.58-2.54 (2H,m), 2.49-2.46 (4H, m), 1.90-1.82 (2H, m). LCMS (ES⁺) RT 2.34 minutes,541 (M+H)⁺.

Example 58N-(2-Fluoro-4-iodophenyl)-3-(piperazin-1-ylcarbonyl)thieno[2,3-b]pyridin-2-amine

Piperazine (3.90 g, 45.2 mmol) was dissolved in dry toluene (100 mL)under nitrogen. The mixture was placed in a water bath at 20° C. andtrimethylaluminium (2.0M in toluene, 22.6 mL, 45.2 mmol) added slowly.After 10 minutes, Example 1 (4.00 g, 0.56 mmol) was added. The mixturewas heated to 100° C. under nitrogen for 6 hours. After cooling to roomtemperature, the mixture was poured onto a slurry of silica (100 g) inchloroform (400 mL) and methanol (200 mL). After agitation for 10minutes, the mixture was allowed to stand overnight. Filtration, andconcentration of the organic solvent in vacuo, gave crude material,which was purified by triturating with diethyl ether (50 mL), filteringand washing with diethyl ether (20 mL). The title compound was isolatedas a yellow solid (3.56 g, 82%), which could be used for furtherchemistry. The dihydrochloride salt of the title compound was preparedby dissolving the free base (1.60 g, 3.32 mmol) in dichloromethane (30mL) and methanol (5 mL). HCl in ether (2.0M, 3.34 mL, 6.70 mmol) wasadded and the mixture concentrated in vacuo. Trituration with diethylether (40 mL) and filtration gave the dihydrochloride salt of the titlecompound (1.80 g, 98%). δ_(H) (DMSO-d₆) 9.75 (0.25H, br s), 9.43 (1.75H,br s), 9.30 (1H, s), 8.36 (1H, dd, J 1.6, 4.7 Hz), 7.87 (1H, dd, J 1.6,8.1 Hz), 7.72 (1H, dd, J 1.9, 10.6 Hz), 7.53 (1H, m), 7.39 (1H, dd, J4.7, 8.1 Hz), 7.22 (1H, dd, J 8.5, 8.5 Hz), 3.75-3.58 (4H, m), 3.17-3.06(4H, m). LCMS (ES⁺) RT 2.19 minutes, 483 (M+H)⁺.

Example 59 Ethyl[4-({2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}1carbonyl)-piperazin-1-yl]acetate

Example 58 (300 mg, 0.62 mmol) was dissolved in dichloromethane (10 mL)and triethylamine (94 μL, 0.65 mmol) and ethyl chloroacetate (56 μL,0.65 mmol) added. The mixture was heated to reflux for 12 hours. Aftercooling and partitioning between dichloromethane and water (25 mL each),the organic layer was dried (Na₂SO₄) and concentrated in vacuo.Purification by chromatography (silica, 3% methanol, 97%dichloromethane) gave the product as an oil, which was dissolved indiethyl ether (5 mL) and concentrated under high vacuum to give thetitle compound as a white solid (240 mg, 68%). δ_(H) (CDCl₃) 9.11 (1H,br s), 8.37 (1H, dd, J 1.5, 4.7 Hz), 7.71 (1H, dd, J 1.5, 8.1 Hz),7.53-7.49 (2H, m), 7.40 (1H, dd, J 8.4, 8.4 Hz), 7.32-7.28 (1H, m), 4.21(2H, q, J 7.1 Hz), 3.75-3.61 (4H, m), 3.31 (2H, s), 2.79-2.62 (4H, m),1.29 (3H, t, J 7.1 Hz). LCMS (ES⁺) RT 3.26 minutes, 569 (M+H)⁺.

Example 60[4-({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}carbonyl)piperazin-1-yl]aceticAcid

Example 59 (213 mg, 0.375 mmol) was dissolved in ethanol (7 mL) andwater (7 mL). Sodium hydroxide (15.0 mg, 0.375 mmol) was added and themixture stirred at room temperature for 18 hours. Freeze-drying gave thetitle compound as its sodium salt (200 mg, 99%). δ_(H) (DMSO-d₆) 9.29(1H, br s), 8.22-8.17 (1H, br m), 7.68 (1H, br d, J 8.0 Hz), 7.56 (1H,br d, J 10.4 Hz), 7.40 (1H, br d, J 8.6 Hz), 7.28-7.20 (1H, br m), 7.07(1H, dd, J 8.6, 8.6 Hz), 3.42-3.38 (4H, m), 2.65 (2H, s), 2.37-2.35 (4H,m). LCMS (ES⁺) RT 2.64 minutes, 541 (M+H)⁺.

Example 61 tert-Butyl(3R)-3-[({2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-carbonyl)amino]pyrrolidine-1-carboxylate

Prepared from Example 1 (250 mg, 0.56 mmol) and(R)-3-amino-1-tert-butoxycarbonylpyrrolidine (417 mg, 2.24 mmol) by themethod of Example 5. After chromatography (25% ethyl acetate, 75%dichloromethane) the title compound was obtained as an off-white solid(45 mg, 13%). δ_(H) (DMSO-d₆) 10.27 (1H, br s), 8.35 (1H, dd, J 1.4, 4.7Hz), 8.23 (1H, br d, J 6.5 Hz), 8.06 (1H, dd, J 1.4, 8.2 Hz), 7.74 (1H,dd, J 1.9, 10.5 Hz), 7.57 (1H, d, J 8.5 Hz), 7.43 (1H, dd, J 4.7, 8.2Hz), 7.36 (1H, dd, J 8.6, 8.6 Hz), 4.46-4.40 (1H, br m), 3.57-3.54 (1H,m), 3.52-3.30 (3H, m), 2.15-2.05 (1H, br m), 1.95-1.85 (1H, br m), 1.41(9H, s). LCMS (ES⁺) RT 3.70 minutes, 583 (M+H)⁺.

Example 62 tert-Butyl(3S)-3-[({2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-carbonyl)amino]pyrrolidine-1-carboxylate

Prepared from Example 1 (250 mg, 0.56 mmol) and(S)-3-amino-1-tert-butoxycarbonylpyrrolidine (417 mg, 2.24 mmol) by themethod of Example 5. After chromatography (25% ethyl acetate, 75%dichloromethane) the title compound was obtained as an off-white solid(190 mg, 58%). δ_(H) (DMSO-d₆) 10.27 (1H, br s), 8.35 (1H, dd, J 1.4,4.7 Hz), 8.23 (1H, br d, J 6.5 Hz), 8.06 (1H, dd, J 1.4, 8.2 Hz), 7.74(1H, dd, J 1.9, 10.5 Hz), 7.57 (1H, d, J 8.5 Hz), 7.43 (1H, dd, J 4.7,8.2 Hz), 7.36 (1H, dd, J 8.6, 8.6 Hz), 4.46-4.40 (1H, br m), 3.57-3.54(1H, m), 3.52-3.30 (3H, m), 2.15-2.05 (1H, br m), 1.95-1.85 (1H, br m),1.41 (9H, s). LCMS (ES⁺) RT 3.70 minutes, 583 (M+H)⁺.

Example 632-[(2-Fluoro-4-iodophenyl)amino]-N-[(3R)-pyrrolidin-3-yl]thieno[2,3-b]pyridine-3-carboxamide

Example 61 (40 mg, 0.069 mmol) was dissolved in dichloromethane (3 mL)and HCl in dioxane (4.0M, 1.0 mL, 4.0 mmol) was added. The mixture wasstirred at room temperature for 18 hours. The resultant solid wasfiltered off and dried under vacuum at 40° C. to give thedihydrochloride salt of the title compound (28 mg, 73%). δ_(H) (DMSO-d₆)10.44 (1H, br s), 9.25 (2H, br m), 8.37-8.31 (2H, m), 8.21 (1H, dd, J1.3, 8.2 Hz), 7.76 (1H, dd, J 1.8, 10.4 Hz), 7.61 (1H, d, J 8.5 Hz),7.45-7.39 (2H, m), 4.61-4.57 (1H, m), 3.45-3.23 (4H, m), 2.27-2.15 (1H,m), 2.09-1.98 (1H, m). LCMS (ES⁺) RT 2.30 minutes, 483 (M+H)⁺.

Example 642-[(2-Fluoro-4-iodophenyl)amino]-N-[(3S)-pyrrolidin-3-yl]thieno[2,3-b]pyridine-3-carboxamide

Example 62 (170 mg, 0.069 mmol) was dissolved in dichloromethane (4 ml)and HCl in dioxane (4.0M, 4.0 ml, 16.0 mmol) was added. The mixture wasstirred at room temperature for 18 hours. The resultant solid wasfiltered off and dried under vacuum at 40° C. to give thedihydrochloride salt of the title compound (150 mg, 92%). OH (DMSO-d₆)10.44 (1H, br s), 9.25 (2H, br m), 8.37-8.31 (2H, m), 8.21 (1H, dd, J1.3, 8.2 Hz), 7.76 (1H, dd, J 1.8, 10.4 Hz), 7.61 (1H, d, J 8.5 Hz),7.45-7.39 (2H, m), 4.61-4.57 (1H, m), 3.45-3.23 (4H, m), 2.27-2.15 (1H,m), 2.09-1.98 (1H, m). LCMS (ES⁺) RT 2.30 minutes, 483 (M+H)⁺.

Example 652-[(2-Fluoro-4-iodophenyl)amino]-N-(1-methylpiperidin-4-yl)thieno[2,3-b]pyridine-3-carboxamide

Prepared from Example 1 (250 mg, 0.56 mmol) and4-amino-1-methylpiperidine (255 mg, 2.24 mmol) by the method of Example5. After chromatography (10% methanol, 90% dichloromethane) the crudematerial was dissolved in dichloromethane (2 mL) and 2.0M HCl in diethylether (2 mL) was added. The resultant solid was filtered off to give thedihydrochloride salt of the title compound as a yellow solid (145 mg,44%). δ_(H) (DMSO-d₆) 10.62 (1H, br s), 10.37 (0.8H, s), 10.26 (0.2H,s), 8.40-8.36 (1H, m), 8.31-8.28 (0.8H, m), 8.22-8.20 (0.2H, m),8.19-8.16 (0.2H, m), 8.10-8.07 (0.8H, m), 7.75-7.71 (1H, m), 7.59-7.56(1H, m), 7.47-7.31 (2H, m), 4.05 (1H, br m), 3.45-3.05 (5H, m), 2.70(3H, d, J 6.0 Hz), 2.03-1.85 (4H, m). LCMS (ES⁺) RT 2.34 minutes, 511(M+H)⁺.

Example 66

{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-[(2R)-2-(methoxymethyl)-pyrrolidin-1-yl]-methanone

From Intermediate 14 (285 mg, 0.66 mmol), 2M trimethylaluminium inhexane (1.6 mL, 3.30 mmol) and (R)-2-(methoxymethyl)pyrrolidine (383 mg,3.30 mmol) by the method of Example 5, to give the title compound (17mg). δ_(H) (DMSO-d₆) 9.17 (1H, br s), 8.37 (1H, dd, J 4.6, 1.3 Hz), 7.78(1H, d, J 7.7 Hz), 7.76 (1H, dd, J 10.6, 1.8 Hz), 7.46 (1H, d, J 8.5Hz), 7.37 (1H, d, J 8.0, 4.6 Hz), 7.05 (1H, t, J 8.5 Hz), 4.10-4.00 (1H,br m), 3.33-3.01 (7H, br m), 1.90-1.64 (4H, br m). LCMS (ES⁺) RT 3.27minutes, 215 (M+H)⁺.

Example 672-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic Acid(cyclopropylmethyl)amide

From Intermediate 14 (450 mg, 1.05 mmol), 2M trimethylaluminium inhexane (2.6 mL, 5.26 mmol) and (aminomethyl)cyclopropane (374 mg, 5.26mmol) by the method of Example 5, to give the title compound (250 mg).δ_(H) (DMSO-d₆) 10.68 (TH, br s), 8.36 (TH, d, J 3.8 Hz), 8.17 (TH, d, J8.1 Hz), 8.15-8.00 (TH, br m), 7.75 (TH, d, J 10.4 Hz), 7.60 (TH, d, J7.6 Hz), 7.47-7.38 (2H, br m), 3.18 (2H, t, J 6.2 Hz), 1.10-1.03 (TH, brm), 0.47-0.41 (2H, br m), 0.28-0.23 (2H, br m). LCMS (ES⁺) RT 3.54minutes, 468 (M+H)⁺.

Example 682-[(2-Fluoro-4-iodophenyl)amino]-7-oxythieno[2,3-b]pyridine-3-carboxylicacid (N-methoxy-N-methyl)amide

To a solution of Intermediate 16 (260 mg, 1.12 mmol) in DMSO was addedsodium hydride (50 mg, 1.23 mmol), and the reaction stirred for 10minutes. Intermediate 1 (328 mg, 1.18 mmol) was added and the reactionstirred for a further 1 h at ambient temperature. The reaction waspoured onto water and extracted into ethyl acetate. The organic phasewas washed with brine, dried (magnesium sulphate) and concentrated invacuo. The crude product was purified by chromatography (SiO₂; 10%methanol in ethyl acetate) yielding the required product as a paleyellow solid (64 mg). δ_(H) (DMSO-d₆) 9.41 (1H, s), 8.20 (1H, dd, J 5.9,1.0 Hz), 7.74 (1H, dd, J 10.3, 1.9 Hz), 7.57-7.54 (1H, m), 7.48-7.38(2H, m), 7.22 (1H, t, J 8.6 Hz), 3.47 (3H, s), 3.17 (3H, s). LCMS (ES⁺)RT 2.70 minutes, 474 (M+H)⁺.

Example 692-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic Acid(N-methoxy-N-methyl)amide

Example 68 (64 mg, 0.13 mmol) and triphenyl phosphine (177 mg, 0.68mmol) in THF (1 mL) were heated at 65° C. overnight. Phosphorustrichloride (34 mg, 0.39 mmol) was added and the reaction stirred atambient temperature for 90 minutes. The reaction was quenched withsodium hydrogen carbonate solution and the product extracted into DCM,dried (magnesium sulphate) and concentrated in vacuo. After preparativeHPLC, the required product (10 mg) was obtained as an off-white solid.δ_(H) (DMSO-d₆) 9.23 (1H, s), 8.35 (1H, dd, J 4.7, 1.6 Hz), 7.84 (1H,dd, J 8.1, 1.6 Hz), 7.70 (1H, dd, J 10.3, 1.9 Hz), 7.53 (1H, d, J 8.4Hz), 7.37 (1H, dd, J 8.1, 4.7 Hz), 7.22 (1H, t, J 8.6 Hz), 3.47 (3H, s),3.20 (3H, s). LCMS (ES⁺) RT 3.23 minutes, 458 (M+H)⁺.

Example 70{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-[(2R)-2-(hydroxymethyl)-piperazin-1-yl]-methanone

A solution of Example 51 (80 mg, 0.13 mmol) in methanol (2 mL) wastreated with 4M HCl in 1,4-dioxane (5 mL) and stirred at r.t. for 3 h.The reaction mixture was concentrated in vacuo to give a yellow gum,which was dissolved in methanol (20 mL) and water (5 mL), then basifiedto pH 11 with 25% aq. ammonium hydroxide. The aqueous solution wasextracted with DCM (3×25 mL), and the organic extracts were combined,dried (Na₂SO₄), filtered and concentrated in vacuo. The crude productwas subjected to column chromatography (SiO₂, 95:4:1 DCM/methanol/25%aq. ammonium hydroxide) to give the title compound as a mixture of 2rotamers, which were freeze-dried overnight from acetonitrile/water togive a cream-coloured powder (63 mg, 94%). δ_(H) (DMSO-d₆, 120° C.,contains rotamers) 8.37-8.36 (1H, m), 8.29-8.28 (0.44H, m), 8.33 (0.56H,dd, J 1.4, 8.0 Hz), 7.75 (0.44H, dd, J 1.8, 10.0 Hz), 7.68-7.66 (0.44H,m), 7.58 (0.56H, dd, J 1.9, 10.5 Hz), 7.48-7.44 (1H, m), 7.39-7.33 (1H,m), 7.17-7.13 (0.56H, m), 4.31-4.29 (1H, m), 4.00 (1H, m), 3.74-3.60(2H, m), 3.10-2.83 (3H, m), 2.76-2.65 (2H, m), 2.60-2.53 (1H, m). LCMSRT 2.07 and 1.95 minutes, (ES⁺) 513 (M+H)⁺.

When ranges are used herein, for example, for biological activity, suchas binding data, chemical properties, such as chemical formulae, ordosage ranges, all combinations and subcombinations of ranges andspecific embodiments therein are intended to be included.

The disclosures of each patent, patent application and publication citedor described in this document are hereby incorporated herein byreference, in their entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

1. A compound of Formula (I), or a pharmaceutically acceptable salt,solvate or N-oxide thereof:

wherein R¹ is hydrogen, halogen or C₁₋₆ alkyl; R² is halogen or C₁₋₆alkyl; R³ is hydrogen, cyano, —CO₂R^(a), —CONR^(b)R^(c) or—CON(OR^(b))R^(c); R^(a) is C₁₋₆ alkyl; R^(b) is hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₇ cycloalkyl,optionally substituted C₃₋₇ cycloalkyl(C₁₋₆)alkyl, optionallysubstituted aryl, optionally substituted aryl(C₁₋₆)alkyl, optionallysubstituted C₃₋₇ heterocycloalkyl, optionally substituted C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, optionally substituted heteroaryl oroptionally substituted heteroaryl(C₁₋₆)alkyl; R^(c) is hydrogen or C₁₋₆alkyl optionally substituted with one or more hydroxyl groups; or R^(b)and R^(c) are taken together with the nitrogen atom to which they areattached to form a cyclic group selected from optionally substitutedazetidinyl, optionally substituted pyrrolidinyl, optionally substitutedpiperidinyl, optionally substituted morpholinyl, optionally substitutedthiomorpholinyl, optionally substituted piperazinyl, optionallysubstituted homopiperidinyl, optionally substituted homomorpholinyl andoptionally substituted homopiperazinyl.
 2. A compound according to claim1, wherein R^(b) is hydrogen, optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₇ cycloalkyl(C₁₋₆)alkyl, optionallysubstituted C₃₋₇ heterocycloalkyl or optionally substituted C₃₋₇heterocycloalkyl-(C₁₋₆)alkyl.
 3. A compound according to claim 1 whereinR^(b) and R^(c) are taken together with the nitrogen atom to which theyare attached to form a cyclic group selected from optionally substitutedazetidin-1-yl, optionally substituted pyrrolidin-1-yl, optionallysubstituted piperidin-1-yl, optionally substituted morpholin-4-yl,piperazin-1-yl and optionally substituted homopiperazin-1-yl.
 4. Acompound according to claim 1 wherein R^(b) or the cyclic group formedby R^(b) and R^(c) and the nitrogen atom to which they are attached isoptionally substituted with one or more of C₁₋₆ alkyl, C₁₋₆alkoxy(C₁₋₆)alkyl, hydroxy, hydroxy(C₁₋₆)alkyl, amino, amino(C₁₋₆)alkyl,carboxymethyl, C₂₋₆ alkoxycarbonyl, C₂₋₆ alkoxycarbonyl-(C₁₋₆)alkyl,di(C₁₋₆)alkylamino, C₂₋₆ alkoxycarbonylamino or C₂₋₆alkoxycarbonylamino(C₁₋₆)alkyl.
 5. A compound according to claim 4wherein R^(b) or the cyclic group formed by R^(b) and R^(c) and thenitrogen atom to which they are attached is substituted with C₁₋₆ alkyl,C₁₋₆ alkoxy(C₁₋₆)alkyl, hydroxy, hydroxy(C₁₋₆)alkyl, amino,amino(C₁₋₆)alkyl, carboxymethyl, C₂₋₆ alkoxycarbonyl, C₂₋₆alkoxycarbonyl(C₁₋₆)alkyl, di(C₁₋₆)alkylamino, C₂₋₆ alkoxycarbonylaminoor C₂₋₆ alkoxycarbonylamino(C₁₋₆)alkyl.
 6. A compound or apharmaceutically acceptable salt, solvate or N-oxide thereof accordingto claim 1, having the following Formula (II):

wherein R³ is hydrogen, cyano, —CO₂R^(a), —CONR^(b)R^(c) or—CON(OR^(b))R^(c); R^(a) is C₁₋₆ alkyl; R^(b) is hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₇ cycloalkyl,optionally substituted C₃₋₇ cycloalkyl(C₁₋₆)alkyl, optionallysubstituted aryl, optionally substituted aryl(C₁₋₆)alkyl, optionallysubstituted C₃₋₇ heterocycloalkyl, optionally substituted C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, optionally substituted heteroaryl oroptionally substituted heteroaryl(C₁₋₆)alkyl; R^(c) is hydrogen or C₁₋₆alkyl optionally substituted with one or more hydroxyl groups; or R^(b)and R^(c) are taken together with the nitrogen atom to which they areattached to form optionally substituted azetidinyl, optionallysubstituted pyrrolidinyl, optionally substituted piperidinyl, optionallysubstituted morpholinyl, optionally substituted thiomorpholinyl,optionally substituted piperazinyl, optionally substitutedhomopiperidinyl, optionally substituted homomorpholinyl or optionallysubstituted homopiperazinyl; and R¹² is halogen.
 7. A compound accordingto claim 6 wherein R¹² is bromo or iodo.
 8. A compound or apharmaceutically acceptable salt, solvate or N-oxide thereof accordingto claim 1, which is selected from the group consisting of: Ethyl2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylate;2-[(2-Fluoro-4-iodophenyl)amino]-N-methylthieno[2,3-b]pyridine-3-carboxamide;2-[(2-Fluoro-4-iodophenyl)amino]-N,N-dimethylthieno[2,3-b]pyridine-3-carboxamide;N-(2-Fluoro-4-iodophenyl)-3-(morpholin-4-ylcarbonyl)thieno[2,3-b]pyridin-2-amine;N-(2-Fluoro-4-iodophenyl)-3-[(4-methylpiperazin-1-yl)carbonyl]thieno[2,3-b]-pyridin-2-amine;2-[(4-Bromo-2-fluorophenyl)amino]-N-(2,3-dihydroxypropyl)thieno[2,3-b]-pyridine-3-carboxamide;2-[(2-Fluoro-4-iodophenyl)amino]-N-(2,3-dihydroxypropyl)thieno[2,3-b]pyridine-3-carboxamide;Ethyl2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylate7-oxide;N-(2,3-Dihydroxypropyl)-2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxamide7-oxide;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonitrile;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acidamide;[2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl](pyrrolidin-1-yl)methanone;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid(3-hydroxypropyl)amide;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid(2(S),3-dihydroxypropyl)amide;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid(2(R),3-dihydroxypropyl)amide;2-[(4-Bromo-2-fluorophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acidmethylamide; 2-[(4-Iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylicacid ethyl ester;2-[(4-Iodo-2-methylphenyl)amino]thieno[2,3-b]pyridine-3-carbonitrile;2-[(4-Bromo-2-fluorophenyl)amino]thieno[2,3-b]pyridine-3-carbonitrile;2-[(2-Chloro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonitrile;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid(2-amino-2-methylpropyl)amide;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid[(4R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]amide;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid[(2R)-2,3-dihydroxypropoxy]amide;(1-{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}piperidin-4-yl)-carbamicacid tert-butyl ester;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid(4-aminopiperidin-1-yl)amide dihydrochloride;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid(2-hydroxy-1-methylethyl)amide;3-[({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}amino)-methyl]azetidine-1-carboxylicacid tert-butyl ester;(1-{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}azetidin-3-ylmethyl)carbamicacid tert-butyl ester;3-({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}amino)-azetidine-1-carboxylicacid tert-butyl ester;[3-(Aminomethyl)azetidin-1-yl]-{2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}methanone;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid[(2R)-pyrrolidin-2-ylmethyl]amide;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid[(2S)-pyrrolidin-2-ylmethyl]amide;(3S)-3-({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}-amino)-piperidine-1-carboxylicacid tert-butyl ester;(3R)-3-({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}-amino)piperidine-1-carboxylicacid tert-butyl ester;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid[(3S)-piperidin-3-yl]amide dihydrochloride;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid[(3R)-piperidin-3-yl]amide dihydrochloride;(1-{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}-(3R)-pyrrolidin-3-yl)carbamicacid tert-butyl ester;(1-{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}-(3S)-pyrrolidin-3-yl)carbamicacid tert-butyl ester;(1-{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}azetidin-3-yl)-carbamicacid tert-butyl ester;4-({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}amino)-piperidine-1-carboxylicacid tert-butyl ester;[(3R)-3-Aminopyrrolidin-1-yl]-{2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]-pyridin-3-yl}methanone;[(3S)-3-Aminopyrrolidin-1-yl]-{2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]-pyridin-3-yl}methanone;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid(piperidin-4-yl)amide;(3-Aminoazetidin-1-yl)-{2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl]methanone;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acidbis(2-hydroxyethyl)amide;{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-(3-hydroxyazetidin-1-yl)-methanone;{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-[(3R)-3-hydroxypyrrolidin-1-yl]-methanone;{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-[(3S)-3-hydroxypyrrolidin-1-yl]-methanone;{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-[2-(hydroxylmethyl)piperidin-1-yl]-methanone;{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-[(3S)-3-(hydroxylmethyl)-morpholin-4-yl]-methanone;4-{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonyl}-(3R)-3-(hydroxymethyl)piperazine-1-carboxylicacid tert-butyl ester;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-7-oxide;2-[(2-Fluoro-4-iodophenyl)amino]-N-[2-(morpholin-4-yl)ethyl]thieno[2,3-b]-pyridine-3-carboxamide;2-[4-({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}carbonyl)-piperazin-1-yl]ethanol;3-(1,4-Diazepan-1-ylcarbonyl)-N-(2-fluoro-4-iodophenyl)thieno[2,3-b]pyridin-2-amine;N-[3-(Dimethylamino)-2,2-dimethylpropyl]-2-[(2-fluoro-4-iodophenyl)amino]-thieno[2,3-b]pyridine-3-carboxamide;2-[(2-Fluoro-4-iodophenyl)amino]-N-[3-(morpholin-4-yl)propyl]thieno[2,3-b]-pyridine-3-carboxamide;N-(2-Fluoro-4-iodophenyl)-3-(piperazin-1-ylcarbonyl)thieno[2,3-b]pyridin-2-amine;Ethyl[4-({2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}carbonyl)-piperazin-1-yl]acetate;[4-({2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}carbonyl)-piperazin-1-yl]aceticacid; tert-Butyl(3R)-3-[({2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-carbonyl)amino]pyrrolidine-1-carboxylate;tert-Butyl(3S)-3-[({2-[(2-fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-carbonyl)amino]pyrrolidine-1-carboxylate;2-[(2-Fluoro-4-iodophenyl)amino]-N-[(3R)-pyrrolidin-3-yl]thieno[2,3-b]pyridine-3-carboxamide;2-[(2-Fluoro-4-iodophenyl)amino]-N-[(3S)-pyrrolidin-3-yl]thieno[2,3-b]pyridine-3-carboxamide;2-[(2-Fluoro-4-iodophenyl)amino]-N-(1-methylpiperidin-4-yl)thieno[2,3-b]-pyridine-3-carboxamide;{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-[(2R)-2-(methoxymethyl)-pyrrolidin-1-yl]-methanone;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid(cyclopropylmethyl)amide;2-[(2-Fluoro-4-iodophenyl)amino]-7-oxythieno[2,3-b]pyridine-3-carboxylicacid (N-methoxy-N-methyl)amide;2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carboxylic acid(N-methoxy-N-methyl)amide; and{2-[(2-Fluoro-4-iodophenyl)amino]thieno[2,3-b]pyridin-3-yl}-[(2R)-2-(hydroxymethyl)-piperazin-1-yl]-methanone.9. A pharmaceutical composition comprising a compound or apharmaceutically acceptable salt, solvate or N-oxide thereof accordingto claim 1, in combination with a pharmaceutically acceptable carrier.10. A method for the treatment or prevention of a disorder for which theadministration of a selective MEK inhibitor is indicated which comprisesadministering to a patient in need of such treatment an effective amountof a compound or a pharmaceutically acceptable salt, solvate or N-oxidethereof according to claim
 1. 11. A method according to claim 10 whereinthe disorder is selected from the group consisting of an autoimmune orinflammatory disorder, a cardiovascular disorder, a proliferativedisorder, an oncological disorder, and pain or a nociceptive disorder.12. A method according to claim 11 wherein the disorder is an autoimmuneor inflammatory disorder.
 13. A method according to claim 12 wherein theautoimmune or inflammatory disorder is selected from the groupconsisting of rheumatoid arthritis, osteoarthritis, multiple sclerosis,asthma, inflammatory bowel disease, psoriasis and transplant rejection.14. A method according to claim 11 wherein the disorder is acardiovascular disorder.
 15. A method according to claim 14 wherein thecardiovascular disorder is selected from the group consisting ofthrombosis, cardiac hypertrophy, hypertension and irregularcontractility of the heart.
 16. A method according to claim 11 whereinthe disorder is a proliferative disorder.
 17. A method according toclaim 16 wherein the proliferative disorder is restenosis.
 18. A methodaccording to claim 11 wherein the disorder is an oncological disorder.19. A method according to claim 18 wherein the oncological disorder isselected from the group consisting of leukemia, glioblastoma, lymphoma,melanoma, and human cancers of the liver, bone, skin, brain, pancreas,lung, breast, stomach, colon, rectum, prostate, ovary and cervix.
 20. Amethod according to claim 11 wherein the disorder is pain or anociceptive disorder.
 21. A method according to claim 20 wherein thepain or nociceptive disorder is selected from the group consisting ofchronic pain and neuropathic pain.